Novel 2-amino-quinazoline derivatives useful as inhibitors of beta-secretase (BACE)

ABSTRACT

The present invention is directed to novel 2-amino-3,4-dihydro-quinazoline derivatives, pharmaceutical compositions containing them and their use in the treatment of Alzheimer&#39;s disease (AD) and related disorders. The compounds of the invention are inhibitors of β-secretase, also known as β-site cleaving enzyme and BACE.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 60/599,811, filed on Aug. 06, 2004, U.S. Provisonal Application Ser.No. 60/599,317, filed on Aug. 06, 2004, and U.S. Provisional ApplicationSer. No. 60/599,810, filed on Aug. 06, 2004, which are incorporated byreference herein in their entirety.

FIELD OF THE INVENTION

The present invention is directed to novel2-amino-3,4-dihydro-quinazoline derivatives, pharmaceutical compositionscontaining them and their use in the treatment of Alzheimer's disease(AD), mild cognitive impairment, senility and/or dementia. The compoundsof the present invention are inhibitors of β-secretase, also known asβ-site amyloid cleaving enzyme, BACE, BACE1, Asp2, or memapsin2.

BACKGROUND OF THE INVENTION

Alzheimer's Disease (AD) is a neurodegenerative disease associated withaging. AD patients suffer from cognition deficits and memory loss aswell as behavioral problems such as anxiety. Over 90% of those afflictedwith AD have a sporadic form of the disorder while less than 10% of thecases are familial or hereditary. In the United States, about 1 in 10people at age 65 have AD while at age 85, 1 out of every two individualsare affected with AD. The average life expectancy from the initialdiagnosis is 7-10 years, and AD patients require extensive care eitherin an assisted living facility which is very costly or by familymembers. With the increasing number of elderly in the population, AD isa growing medical concern. Currently available therapies for AD merelytreat the symptoms of the disease and include acetylcholinesteraseinhibitors to improve cognitive properties as well as anxiolytics andantipsychotics to control the behavioral problems associated with thisailment.

The hallmark pathological features in the brain of AD patients areneurofibillary tangles which are generated by hyperphosphorylation oftau protein and amyloid plaques which form by aggregation ofβ-amyloid₁₋₄₂ (Aβ₁₋₄₂) peptide. Aβ₁₋₄₂ forms oligomers and then fibrils,and ultimately amyloid plaques. The fibrils are believed to beespecially neurotoxic and may cause most of the neurological damageassociated with AD. Agents that prevent the formation of Aβ₁₋₄₂ have thepotential to be disease-modifying agents for the treatment of AD. Aβ₁₋₄₂is generated from the amyloid precursor protein (APP), comprised of 770amino acids. The N-terminus of Aβ₁₋₄₂ is cleaved by β-secretase (BACE),and then γ-secretase cleaves the C-terminal end. In addition to Aβ₁₋₄₂,γ-secretase also liberates Aβ₁₋₄₀ which is the predominant cleavageproduct as along with Aβ₁₋₃₈ and Aβ₁₋₄₃. Thus, inhibitors of BACE wouldbe expected to prevent the formation of Aβ₁₋₄₂ and would be potentialtherapeutic agents in the treatment of AD.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of formula (I)

wherein

R⁰ is selected from the group consisting of hydrogen, methyl and CF₃;

R¹ is selected from the group consisting of hydrogen, hydroxy, methyl,ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy andmethyl-carbonyl;

A¹ is selected from the group consisting of C₁₋₄alkyl; wherein theC₁₋₄alkyl is optionally substituted with one or more R^(X) substituents;

wherein each R^(X) is independently selected from the group consistingof hydroxy, oxo, C₁₋₈alkyl, C₁₋₈alkoxy, hydroxy substituted C₁₋₆alkyl,amino substituted C₁₋₆alkyl, cycloalkyl, cycloalkyl-C₁₋₄alkyl-,biphenyl, aryl, C₁₋₄aralkyl, heteroaryl, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl, heterocycloalkyl-C₁₋₄alkyl-, spiro-heterocyclyl and—(C₁₋₄alkyl)_(n)-Q²-R⁴;

wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl group, whether alone or as part of a substituentgroup is optionally substituted with one or more substituentsindependently selected from the group consisting of fluoro, chloro,hydroxy, oxo, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, —C(O)O—(C₁₋₄alkyl),hydroxy substituted C₁₋₄alkyl, fluoro substituted C₁₋₄alkyl, fluorosubstituted C₁₋₄alkoxy, 5-tetrazolyl and 1-(1,4-dihydro-tetrazol-5-one);

wherein n is an integer from 0 to 1;

wherein Q² is selected from the group consisting of —O—, —S—, —C(O)—,—C(S)—, —C(O)O—, —OC(O)—, —NR^(G)—, —NR^(G)—C(O)—, —C(O)—NR^(G)—,—NR^(G)—SO₂—, —SO—NR^(G)—, —NR^(G)—SO—, —SO—NR^(G), —NR^(G)—C(O)O—,—OC(O)—NR^(G)—, —O—SO₂—NR^(G)—, —NR^(G)—SO₂—O—, —NR^(G)—C(O)—NR^(H)—,—NR^(G)—C(S)—NR^(H)— and —NR^(G)—SO₂—NR^(H)—;

wherein each R^(G) and R^(H) is independently selected from the groupconsisting of hydrogen, C₁₋₈alkyl, hydroxy substituted C₁₋₄alkyl,C₁₋₄aralkyloxy substituted C₁₋₄alkyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl,heteroaryl-C₁₋₄alkyl-, heterocycloalkyl-C₁₋₄alkyl- andspiro-heterocyclyl;

wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl, whether alone or as part of a substituent group isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy-carbonyl, nitro, cyano, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, —SO₂—N(R^(J)R^(K)), 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one);

wherein each R^(J) and R^(K) is independently selected from from thegroup consisting of hydrogen and C₁₋₄alkyl;

wherein R⁴ is selected from the group consisting of hydrogen, C₁₋₄alkyl,hydroxy substituted C₁₋₄alkyl, fluoro substituted C₁₋₄alkyl, cycloalkyl,aryl, biphenyl, heteroaryl, heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-,C₁₋₄aralkyl, heteroaryl-C₁₋₄alkyl-, heterocycloalkyl-C₁₋₄alkyl- andspiro-heterocyclyl;

wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl, whether alone or as part of a substituent group isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,—C(O)O—C₁₋₄alkyl, —C(O)—C₁₋₄alkyl, C₁₋₄alkyl, fluoro substitutedC₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino and phenyl;

wherein the phenyl is optionally substituted with one or moresubstituent independently selected from the group consisting of halogen,hydroxy, oxo, carboxy, —C(O)O—C₁₋₄alkyl, —C(O)—C₁₋₄alkyl, C₁₋₄alkyl,fluoro substituted C₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino and —SO₂—N(R^(E)R^(F));

wherein each R^(E) and R^(F) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

Q¹ is selected from the group consisting of —O—, —S—, —C(O)—, —C(S)—,—C(O)O—, —OC(O)—, —NR^(A)—, —NR^(A)—C(O)—, —C(O)—NR^(A)—, —NR^(A)—C(S)—,—C(S)—NR^(A)—, —NR^(A)—SO₂—, —SO₂—NR^(A)—, —NR^(A)—SO—, —SO—NR^(A),—NR^(A)—C(O)O—, —OC(O)—NR^(A)—, —O—SO₂—NR^(A)—, —NR^(A)—SO₂—O—,—NR^(A)—C(O)—NR^(B)—, —NR^(A)—C(S)—NR^(B)— and —NR^(A)—SO₂—NR^(B)—;

wherein each R^(A) and R^(B) is independently selected from the groupconsisting of hydrogen, C₁₋₈alkyl, hydroxy substituted C₁₋₄alkyl,C₁₋₄aralkyloxy substituted C₁₋₄alkyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl,heteroaryl-C₁₋₄alkyl-, heterocycloalkyl-C₁₋₄alkyl- andspiro-heterocyclyl;

wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl, whether alone or as part of a substituent group isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy-carbonyl, nitro, cyano, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, —SO₂—N(R^(C)R^(D)), 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one);

wherein each R^(C) and R^(D) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

R² is selected from the group consisting of C₁₋₁₀alkyl, cycloalkyl,aryl, biphenyl, partially unsaturated carbocyclyl, heteroaryl,heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl, partiallyunsaturated carbocyclyl-C₁₋₄alkyl-, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl;

wherein the C₁₋₁₀alkyl, cycloalkyl, aryl, partially unsaturatedcarbocyclyl, heteroaryl, heterocycloalkyl or spiro-heterocyclyl, whetheralone or as part of a substituent group is optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, hydroxy, oxo, carboxy, —C(O)—C₁₋₄alkyl,—C(O)—C₁₋₄aralkyl, —C(O)O—C₁₋₄alkyl, —C(O)O—C₁₋₄aralkyl,—C₁₋₄alkyl-C(O)O—C₁₋₄alkyl, —C₁₋₄alkyl-S—C₁₋₄alkyl, —C(O)—N(R^(L)R^(M)),—C₁₋₄alkyl-C(O)—N(R^(L)R^(M)), —NR^(L)—C(O)—C₁₋₄alkyl,—SO₂—N(R^(L)R^(M)), —C₁₋₄alkyl-SO₂—N(R^(L)R^(M)), C₁₋₆alkyl, fluorosubstituted C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, carboxysubstituted C₁₋₄alkyl, C₁₋₄alkoxy, —O—C₁₋₄aralkyl,—O-(tetrahydropyranyl), —NH—C(O)O—CH₂-(tetrahydropyranyl),—N(CH₃)—C(O)O—CH₂-(tetrahydropyranyl), nitro, cyano, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, phenyl, 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one);

wherein the phenyl or tetrahydropyranyl is optionally substituted withone or more substituent independently selected from the group consistingof halogen, hydroxy, oxo, carboxy, —C(O)O—C₁₋₄alkyl, —C(O)—C₁₋₄alkyl,—OC(O)—C₁₋₄alkyl, —C₁₋₄alkyl-OC(O)—C₁₋₄alkyl, —O—C₁₋₄aralkyl, C₁₋₄alkyl,fluoro substituted C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, C₁₋₄alkoxy,nitro, cyano, amino, C₁₋₄alkylamino and di(C₁₋₄alkyl)amino;

wherein each R^(L) and R^(M) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

b is an integer from 0 to 1;

L¹ is selected from the group consisting of —O—, —S(O)₀₋₂—, —NR^(N)—,—C(O)—, —C(S)—, —C₁₋₄alkyl-, -(hydroxy substituted C₁₋₄alkyl)- and—(C₂₋₄alkenyl)-;

wherein R^(N) is selected from the group consisting of hydrogen andC₁₋₄alkyl;

R³ is selected from the group consisting of C₁₋₆alkyl, C₂₋₆alkenyl,cycloalkyl, partially unsaturated carbocyclyl, aryl, biphenyl,heteroaryl, heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl,heteroaryl-C₁₋₄alkyl-, heterocycloalkyl-C₁₋₄alkyl- andspiro-heterocyclyl;

wherein the C₁₋₆alkyl, cycloalkyl, partially unsaturated carbocyclyl,aryl, heteroaryl, heterocycloalkyl or spiro-heterocyclyl, whether aloneor as part of a substituent group is optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, hydroxy, oxo, carboxy, C₁₋₄alkyl, hydroxy substitutedC₁₋₄alkyl, halogen substituted C₁₋₄alkyl, cyano substituted C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, halogen substituted C₁₋₄alkoxy,nitro, cyano, —R⁵, —O—R⁵, —S—R⁵, —SO₂—R⁵, —SO₂—NR^(P)—R⁵,—NR^(P)—SO₂—R⁵, —NH₂, —N(R^(P))—R⁵, —C(O)—R⁵, —C(O)—NH₂,—C(O)—NR^(P)—R⁵, —NR^(P)—C(O)—R⁵ and —NR^(P)—C(O)O—R⁵;

wherein R⁵ is selected from the group consisting of C₁₋₄alkyl, aryl,C₁₋₄aralkyl, partially unsaturated carbocyclyl, cycloalkyl,cycloalkyl-C₁₋₄alkyl-, partially unsaturated carbocyclyl-C₁₋₄alkyl-,heteroaryl, heteroaryl-C₁₋₄alkyl-, heterocycloalkyl andheterocyclyl-C₁₋₄alkyl-;

wherein the aryl, partially unsaturated carbocyclyl, cycloalkyl,heteroaryl or heterocycloalkyl, whether alone or as part of asubstituent group is optionally substituted with one or more substituentindependently selected from the group consisting of C₁₋₄alkyl,C₁₋₄alkoxy, halogen, hydroxy, carboxy, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, cyano and nitro;

wherein R^(P) is selected from the group consisting of hydrogen,C₁₋₈alkyl, hydroxy substituted C₁₋₄alkyl, C₁₋₄aralkyloxy substitutedC₁₋₄alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl,cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl;

wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl, whether alone or as part of a substituent group isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy-carbonyl, nitro, cyano, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, —SO₂—N(R^(S)R^(T)), 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one);

wherein each R^(S) and R^(T) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

a is an integer from 0 to 3;

each R¹⁰ is independently selected from the group consisting of hydroxy,halogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen substituted C₁₋₄alkyl, halogensubstituted C₁₋₄alkoxy, —C(O)—NR^(V)R^(W), —SO₂—NR^(V)R^(W),—C(O)—C₁₋₄alkyl and —SO₂—C₁₋₄alkyl;

wherein each R^(V) and R^(W) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl; alternatively R^(V) and R^(W) aretaken together with the N atom to which they are bound to form a 5 to 6membered saturated, partially unsaturated or aromatic ring structure;

provided that the halogens on the halogen substituted C₁₋₄alkyl or thehalogen substituted C₁₋₄alkoxy are selected from the group consisting ofchloro and fluoro;

provided that when R⁰ is hydrogen, R¹ is hydrogen, b is 1, L¹ is —O—, R³is C₃alkyl, wherein the C₃alkyl is substituted with —C(O)—NR^(P)—R⁵,wherein R^(P) is methyl and R⁵ is cyclohexyl, A¹ is —CH₂— and Q¹ is—C(O)—O—, then R² is other than C₁₋₆alkyl, cycloalkyl or C₁₋₄aralkyl;

provided further that when R⁰ is hydrogen, R¹ is hydrogen, b is 1, L¹ is—O—, R³ is C₃alkyl, wherein the C₃alkyl is substituted with—C(O)—NR^(P)—R⁵, wherein R^(P) is methyl and R⁵ is cyclohexyl, A¹ is—CH₂— and Q¹ is —C(O)—, then R² is other than morpholinyl orpiperidinyl;

provided further that when R⁰ is hydrogen, R¹ is hydrogen, b is 1, L¹ is—O—, R³ is C₃alkyl, wherein the C₃alkyl is substituted with—C(O)—NR^(P)—R⁵, wherein R^(P) is methyl and R⁵ is cyclohexyl, A¹ is—CH₂— and Q¹ is —C(O)—NH—, then R² is other than phenyl;

and pharmaceutically acceptable salts thereof.

The present invention is further directed to compounds of formula (II)

wherein

R⁰ is selected from the group consisting of hydrogen, methyl, and CF₃;

R¹ is selected from the group consisting of hydrogen, hydroxy, methyl,ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy andmethyl-carbonyl;

c is an integer from 0 to 1;

A² is selected from the group consisting of C₁₋₄alkyl; wherein theC₁₋₄alkyl is optionally substituted with one or more R^(Y) substituents;

wherein each R^(Y) is independently selected from the group consistingof hydroxy, oxo, C₁₋₄alkyl, C₁₋₄alkoxy, hydroxy substituted C₁₋₄alkyl,amino substituted C₁₋₆alkyl, cycloalkyl, cycloalkyl-C₁₋₄alkyl-,biphenyl, aryl, C₁₋₄aralkyl, heteroaryl, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl, heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl;

wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl group, whether alone or as part of a substituentgroup is optionally substituted with one or more substituentsindependently selected from the group consisting of fluoro, chloro,hydroxy, oxo, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, —C(O)O—(C₁₋₄alkyl),hydroxy substituted C₁₋₄alkyl, fluoro substituted C₁₋₄alkyl, fluorosubstituted C₁₋₄alkoxy, 5-tetrazolyl and 1-(1,4-dihydro-tetrazol-5-one);

is selected from the group consisting of aryl, C₁₋₄aralkyl, cycloalkyl,partially unsaturated carbocyclyl, heteroaryl, heterocycloalkyl andspiro-heterocyclyl;

wherein the aryl, cycloalkyl, partially unsaturated carbocyclyl,heteroaryl, heterocycloalkyl or spiro-heterocyclyl group, whether aloneor as part of a substituent group, is optionally substituted with one ormore substituents independently selected from the group consisting ofC₁₋₄alkyl, C₁₋₄alkoxy, halogen substituted C₁₋₄alkyl, halogensubstituted C₁₋₄alkoxy, hydroxy substituted C₁₋₄alkyl, hydroxy, carboxy,cyano, nitro, amino, C₁₋₄alkylamino and di(C₁₋₄alkyl)amino;

provided that when c is 0 (i.e. A¹ is absent), then

is other than aryl or heteroaryl;

Q³ is selected from the group consisting of —O—, —S—, —C(O)—, —C(S)—,—C(O)O—, —OC(O)—, —C(O)—NR^(A) , —NR^(A)—C(O)—, —C(S)—NR^(A),—SO₂—NR^(A)—, —SO—NR^(A), —OC(O)—NR^(A)—, —NR^(A)—C(O)O— and—O—SO₂—NR^(A)—;

wherein each R^(A) is independently selected from the group consistingof hydrogen, C₁₋₈alkyl, hydroxy substituted C₁₋₄alkyl, C₁₋₄aralkyloxysubstituted C₁₋₄alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl,cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl;

wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl, whether alone or as part of a substituent group isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy-carbonyl-, nitro, cyano, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, —SO₂—N(R^(C)R^(D)), 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one);

wherein each R^(C) and R^(D) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

R² is selected from the group consisting of C₁₋₁₀alkyl, cycloalkyl,aryl, biphenyl, partially unsaturated carbocyclyl, heteroaryl,heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl, partiallyunsaturated carbocyclyl-C₁₋₄alkyl-, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl;

wherein the C₁₋₁₀alkyl, cycloalkyl, aryl, partially unsaturatedcarbocyclyl, heteroaryl, heterocycloalkyl or spiro-heterocyclyl, whetheralone or as part of a substituent group is optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, hydroxy, oxo, carboxy, —C(O)—C₁₋₄alkyl,—C(O)—C₁₋₄aralkyl, —C(O)O—C₁₋₄alkyl, —C(O)O—C₁₋₄aralkyl,—C₁₋₄alkyl-C(O)O—C₁₋₄alkyl, —C₁₋₄alkyl-S—C₁₋₄alkyl, —C(O)—N(R^(L)R^(M)),—C₁₋₄alkyl-C(O)—N(R^(L)R^(M)), —NR^(L)—C(O)—C₁₋₄alkyl,—SO₂—N(R^(L)R^(M)), —C₁₋₄alkyl-SO₂—N(R^(L)R^(M)), C₁₋₆alkyl, fluorosubstituted C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, carboxysubstituted C₁₋₄alkyl, C₁₋₄alkoxy, —O—C₁₋₄aralkyl,—O-(tetrahydropyranyl), —NH—C(O)O—CH₂-(tetrahydropyranyl),—N(CH₃)—C(O)O—CH₂-(tetrahydropyranyl), nitro, cyano, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, phenyl, 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one);

wherein the phenyl or tetrahydropyranyl is optionally substituted withone or more substituent independently selected from the group consistingof halogen, hydroxy, oxo, carboxy, C(O)O—C₁₋₄alkyl, C(O)—C₁₋₄alkyl,—O—C(O)—C₁₋₄alkyl, —C₁₋₄alkyl-OC(O)—C₁₋₄alkyl, —O—C₁₋₄aralkyl,C₁₋₄alkyl, fluoro substituted C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl,C₁₋₄alkoxy, nitro, cyano, amino, C₁₋₄alkylamino and di(C₁₋₄alkyl)amino;

wherein each R^(L) and R^(M) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

b is an integer from 0 to 1;

L¹ is selected from the group consisting of —O—, —S(O)₀₋₂—, —NR^(N)—,—C(O)—, —C(S)—, —C₁₋₄alkyl-, -(hydroxy substituted C₁₋₄alkyl)- and—(C₂₋₄alkenyl)-;

wherein R^(N) is selected from the group consisting of hydrogen andC₁₋₄alkyl;

R³ is selected from the group consisting of C₁₋₆alkyl, C₂₋₆alkenyl,cycloalkyl, partially unsaturated carbocyclyl, aryl, biphenyl,heteroaryl, heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl,heteroaryl-C₁₋₄alkyl-, heterocycloalkyl-C₁₋₄alkyl- andspiro-heterocyclyl;

wherein the C₁₋₆alkyl, cycloalkyl, partially unsaturated carbocyclyl,aryl, heteroaryl, heterocycloalkyl or spiro-heterocyclyl, whether aloneor as part of a substituent group is optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, hydroxy, oxo, carboxy, C₁₋₄alkyl, hydroxy substitutedC₁₋₄alkyl, halogen substituted C₁₋₄alkyl, cyano substituted C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, halogen substituted C₁₋₄alkoxy,nitro, cyano, —R⁵, —O—R⁵, —S—R⁵, —SO₂—R⁵, —SO₂—NR^(P)—R⁵,—NR^(A)—SO₂—R⁵, —NH₂, —N(R^(P))—R⁵, —C(O)—R⁵, —C(O)—NH₂,—C(O)—NR^(P)—R⁵, —NR^(P)—C(O)—R⁵ and —NR^(P)—C(O)O—R⁵;

wherein R⁵ is selected from the group consisting of C₁₋₄alkyl, aryl,C₁₋₄aralkyl, partially unsaturated carbocyclyl, cycloalkyl,cycloalkyl-C₁₋₄alkyl-, partially unsaturated carbocyclyl-C₁₋₄alkyl-,heteroaryl, heteroaryl-C₁₋₄alkyl-, heterocycloalkyl andheterocyclyl-C₁₋₄alkyl-;

wherein the aryl, partially unsaturated carbocyclyl, cycloalkyl,heteroaryl or heterocycloalkyl, whether alone or as part of asubstituent group is optionally substituted with one or more substituentindependently selected from the group consisting of C₁₋₄alkyl,C₁₋₄alkoxy, halogen, hydroxy, carboxy, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, cyano and nitro;

wherein R^(P) is selected from the group consisting of hydrogen,C₁₋₈alkyl, hydroxy substituted C₁₋₄alkyl, C₁₋₄aralkyloxy substitutedC₁₋₄alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl,cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl;

wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl, whether alone or as part of a substituent group isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy-carbonyl, nitro, cyano, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, —SO₂—N(R^(S)R^(T)), 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one);

wherein each R^(S) and R^(T) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

a is an integer form 0 to 3;

each R¹⁰ is independently selected from the group consisting of hydroxy,halogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen substituted C₁₋₄alkyl, halogensubstituted C₁₋₄alkoxy, —C(O)—NR^(V)R^(W), —SO₂—NR^(V)R^(W),—C(O)—C₁₋₄alkyl and —SO₂—C₁₋₄alkyl;

wherein each R^(V) and R^(W) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl; alternatively R^(V) and R^(W) aretaken together with the N atom to which they are bound to form a 5 to 6membered saturated, partially unsaturated or aromatic ring structure;

provided that the halogens on the halogen substituted C₁₋₄alkyl and thehalogen substituted C₁₋₄alkoxy are selected from the group consisting ofchloro and fluoro;

provided that when R⁰ is hydrogen, R¹ is hydrogen, A¹ is —CH₂—,

is phenyl, Q³ is —O—, R² is methyl, b is an integer selected from 0 to 1and L¹ is selected from —O—, —NH— or —N(CH₃)—, then R³ is other thanmethyl;

and pharmaceutically acceptable salts thereof.

The present invention is further directed to compounds of formula (III)

wherein

R⁰ is selected from the group consisting of hydrogen, methyl and CF₃;

R¹ is selected from the group consisting of hydrogen, hydroxy, methyl,ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy andmethyl-carbonyl;

R⁶ is selected from the group consisting of C₁₋₆alkyl and hydroxysubstituted C₁₋₈alkyl;

d is an integer from 0 to 1;

L² is selected from the group consisting of —O—, —S(O)₀₋₂—, —NR^(Q)—;

wherein R^(Q) is selected from the group consisting of hydrogen andC₁₋₄alkyl;

R⁷ is selected from the group consisting of cycloalkyl,cycloalkyl-C₁₋₄alkyl, aryl, C₁₋₄alkyl-aryl, aryl-C₁₋₄alkyl, partiallyunsaturated carbocyclyl, partially unsaturated carbocyclyl-C₁₋₄alkyl,heteroaryl, heteroaryl-C₁₋₄alkyl, heterocycloalkyl andheterocycloalkyl-C₁₋₄alkyl;

wherein the aryl, cycloalkyl, partially unsaturated carbocyclyl,heteroaryl or heterocycloalkyl group, whether alone or as part of asubstituent group, is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₄alkyl, C₁₋₄alkoxy, halogen substituted C₁₋₄alkyl, halogensubstituted C₁₋₄alkoxy, hydroxy substituted C₁₋₄alkyl, hydroxy, carboxy,cyano, nitro, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, 5-tetrazolyland 1-(1,4-dihydro-tetrazol-5-one);

L³ is selected from the group consisting of —O—, —S—, —C(O)—, —C(S)—,—C(O)O—, —OC(O)—, —NR^(A)—, —N(CN)—, —NR^(A)—C(O)—, —C(O)—NR^(A)—,—NR^(A)—C(S)—, —C(S)—NR^(A)—, —NR^(A)—SO₂—, —SO₂—NR^(A)—, —NR^(A)—SO—,—SO—NR^(A)—, —NR^(A)—C(O)O—, —OC(O)—NR^(A)—, —O—SO₂—NR^(A)—,—NR^(A)—SO₂—O—, NR^(A)—C(O)—NR^(B)—, —NR^(A)—C(S)—NR^(B)— and—NR^(A)—SO₂—NR^(B);

wherein each R^(A) and R^(B) is independently selected from the groupconsisting of hydrogen, C₁₋₈alkyl, hydroxy substituted C₁₋₄alkyl,C₁₋₄aralkyloxy substituted C₁₋₄alkyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl,heteroaryl-C₁₋₄alkyl-, heterocycloalkyl-C₁₋₄alkyl- andspiro-heterocyclyl;

wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl, whether alone or as part of a substituent group isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy-carbonyl, nitro, cyano, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, —SO₂—N(R^(C)R^(D)), 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one);

wherein each R^(C) and R^(D) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

R⁸ is selected from the group consisting of C₁₋₁₀alkyl, cycloalkyl,aryl, biphenyl, partially unsaturated carbocyclyl, heteroaryl,heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl, partiallyunsaturated carbocyclyl-C₁₋₄alkyl-, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl;

wherein the C₁₋₁₀alkyl, cycloalkyl, aryl, partially unsaturatedcarbocyclyl, heteroaryl, heterocycloalkyl or spiro-heterocyclyl, whetheralone or as part of a substituent group is optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, hydroxy, oxo, carboxy, —C(O)—C₁₋₄alkyl,—C(O)—C₁₋₄aralkyl, —C(O)O—C₁₋₄alkyl, —C(O)O—C₁₋₄aralkyl,—C₁₋₄alkyl-C(O)O—C₁₋₄alkyl, —C₁₋₄alkyl-S—C₁₋₄alkyl, —C(O)—N(R^(L)R^(M)),—C₁₋₄alkyl-C(O)—N(R^(L)R^(M)), —NR^(L)—C(O)—C₁₋₄alkyl, —SO₂—C₁₋₄alkyl,—SO₂-aryl, —SO₂—N(R^(L)R^(M)), —C₁₋₄alkyl-SO₂—N(R^(L)R^(M)), C₁₋₄alkyl,fluoro substituted C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, carboxysubstituted C₁₋₄alkyl, C₁₋₄alkoxy, fluoro substituted C₁₋₄alkoxy, nitro,cyano, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, phenyl and heteroaryl;

wherein the phenyl or heteroaryl is optionally substituted with one ormore substituent independently selected from the group consisting ofhalogen, hydroxy, oxo, carboxy, —C(O)O—C₁₋₄alkyl, —C(O)—C₁₋₄alkyl,C₁₋₄alkyl, fluoro substituted C₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano,amino, C₁₋₄alkylamino and di(C₁₋₄alkyl)amino;

wherein each R^(L) and R^(M) is independently selected from the groupconsisting of hydrogen, C₁₋₄alkyl and cycloalkyl;

a is an integer from 0 to 3;

each R¹⁰ is independently selected from the group consisting of hydroxy,halogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen substituted C₁₋₄alkyl, halogensubstituted C₁₋₄alkoxy, —C(O)—NR^(V)R^(W), —SO₂—NR^(V)R^(W),—C(O)—C₁₋₄alkyl and —SO₂—C₁₋₄alkyl;

wherein each R^(V) and R^(W) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl; alternatively R^(V) and R^(W) aretaken together with the N atom to which they are bound to form a 5 to 6membered saturated, partially unsaturated or aromatic ring structure;

provided that the halogens on the halogen substituted C₁₋₄alkyl and thehalogen substituted C₁₋₄alkoxy are selected from the group consisting ofchloro and fluoro;

or a pharmaceutically acceptable salt thereof.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and any of the compounds describedabove. An illustration of the invention is a pharmaceutical compositionmade by mixing any of the compounds described above and apharmaceutically acceptable carrier. Illustrating the invention is aprocess for making a pharmaceutical composition comprising mixing any ofthe compounds described above and a pharmaceutically acceptable carrier.

Exemplifying the invention are methods of treating a disorder mediatedby the β-secretase enzyme, comprising administering to a subject in needthereof, a therapeutically effective amount of any of the compounds orpharmaceutical compositions described above.

An example of the invention is a method of treating a disorder selectedfrom the group consisting of Alzheimer's disease (AD), mild cognitiveimpairment, senility, dementia, dementia with Lewy bodies, Down'ssyndrome, dementia associated with Parkinson's disease and dementiaassociated with beta-amyloid, comprising administering to a subject inneed thereof, a therapeutically effective amount of any of the compoundsor pharmaceutical compositions described above.

Another example of the invention is the use of any of the compoundsdescribed above in the preparation of a medicament for treating: (a)Alzheimer's Disease (AD), (b) mild cognitive impairment, (c) senility,(d) dementia, (e) dementia with Lewy bodies, (f) Down's syndrome, (g)dementia associated with Parkinson's disease and (h) dementia associatedwith beta-amyloid, in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of formula (I), (II) and(III)

wherein R⁰, R¹, R², R³, R⁶, R⁷, R⁸, R¹⁰, L¹, L², L³, a, b, c, d, A¹, A²,Q¹, Q³ and

are as herein defined. The compounds of formula (I), formula (II) andformula (III) are inhibitors of the β-secretase enzyme (also known asβ-site cleaving enzyme, BACE, BACE1, Asp2 or memapsin2), and are usefulin the treatment of Alzheimer's disease (AD), mild cognitive impairment(MCI), senility, dementia, dementia with Lewy bodies, Down's syndrome,dementia associated with Parkinson's disease and dementia associatedwith beta-amyloid, preferably Alzheimer's disease.

One skilled in the art will recognize that some of the variables (e.g.R⁰, R¹, L¹, R², R¹⁰, etc.) appear in compounds of formula (I), formula(II) and t or formula (III). One skilled in the art will furtherrecognize that wherein a particular substituent is selected for a givenvariable for a compound of formula (I), said selection is not intendedto limit the scope of said variable for compounds of formula (II) and/orcompounds of formula (III). Similarly, the selection of a particularsubstituent for a given variable for a compound of formula (II), is notintended to limit the scope of said variable for compounds of formula(I) and/or compounds of formula (III). Similarly, the selection of aparticular substituent for a given variable for a compound of formula(III), is not intended to limit the scope of said variable for compoundsof formula (I) and/or compounds of formula (II).

In an embodiment, the present invention is directed to compounds offormula (I)

wherein

R⁰ is selected from the group consisting of hydrogen, methyl and CF₃;

R¹ is selected from the group consisting of hydrogen, hydroxy, methyl,ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy andmethyl-carbonyl;

A¹ is selected from C₁₋₄alkyl; wherein the C₁₋₄alkyl is optionallysubstituted with one or more R^(X) substituents;

wherein each R^(X) is independently selected from the group consistingof hydroxy, oxo, C₁₋₈alkyl, C₁₋₈alkoxy, hydroxy substituted C₁₋₆alkyl,amino substituted C₁₋₆alkyl, cycloalkyl, cycloalkyl-C₁₋₄alkyl-,biphenyl, aryl, C₁₋₄aralkyl, heteroaryl, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl, heterocycloalkyl-C₁₋₄alkyl-, spiro-heterocyclyl and—(C₁₋₄alkyl)_(n)-Q²-R⁴;

wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl group, whether alone or as part of a substituentgroup is optionally substituted with a substituent selected from thegroup consisting of fluoro, chloro, hydroxy, oxo, carboxy, C₁₋₄alkyl,C₁₋₄alkoxy, —C(O)—(C₁₋₄alkyoxy), hydroxy substituted C₁₋₄alkyl, fluorosubstituted C₁₋₄alkyl, fluoro substituted C₁₋₄alkoxy, 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one);

wherein n is an integer from 0 to 1;

wherein Q² is selected from the group consisting of —O—, —S—, —C(O)—,—C(S)—, —C(O)O—, —OC(O)—, —NR^(G)—, —NR^(G)—C(O)—, —C(O)—NR^(G)—,—NR^(G)—SO₂—, —SO₂—NR^(G)—, —NR^(G)—SO—, —SO—NR^(G), —NR^(G)—C(O)—,—OC(O)—NR^(G)—, —O—SO₂—NR^(G)—, —NR^(G)—SO₂—O—, —NR^(G)—C(O)—NR^(H)—,—NR^(G)—C(S)—NR^(H)— and —NR^(G)—SO₂—NR^(H)—;

wherein each R^(G) and R^(H) is independently selected from the groupconsisting of hydrogen, C₁₋₈alkyl, hydroxy substituted C₁₋₄alkyl,C₁₋₄aralkyloxy substituted C₁₋₄alkyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl,heteroaryl-C₁₋₄alkyl-, heterocycloalkyl-C₁₋₄alkyl- andspiro-heterocyclyl;

wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl, whether alone or as part of a substituent group isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy-carbonyl, nitro, cyano, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, —SO₂—N(R^(J)R^(K)), 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one);

wherein each R^(J) and R^(K) is independently selected from from thegroup consisting of hydrogen and C₁₋₄alkyl;

wherein R⁴ is selected from the group consisting of hydrogen, C₁₋₄alkyl,hydroxy substituted C₁₋₄alkyl, fluoro substituted C₁₋₄alkyl, cycloalkyl,aryl, biphenyl, heteroaryl, heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-,C₁₋₄aralkyl, heteroaryl-C₁₋₄alkyl-, heterocycloalkyl-C₁₋₄alkyl- andspiro-heterocyclyl;

wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl, whether alone or as part of a substituent group isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,—C(O)O—C₁₋₄alkyl, —C(O)—C₁₋₄alkyl, C₁₋₄alkyl, fluoro substitutedC₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino and phenyl;

wherein the phenyl is optionally substituted with one or moresubstituent independently selected from the group consisting of halogen,hydroxy, oxo, carboxy, —C(O)O—C₁₋₄alkyl, —C(O)—C₁₋₄alkyl, C₁₋₄alkyl,fluoro substituted C₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino and —SO₂—N(R^(E)R^(F));

wherein each R^(E) and R^(F) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

Q¹ is selected from the group consisting of —O—, —S—, —C(O)—, —C(S)—,—C(O)O—, —OC(O)—, —NR^(A)—, —NR^(A)—C(O)—, —C(O)—NR^(A)—, —NR^(A)—C(S)—,—C(S)—NR^(A)—, —NR^(A)—SO₂—, —SO₂—NR^(A)—, —NR^(A)—SO—, —SO—NR^(A),—NR^(A)—C(O)O—, —OC(O)—NR^(A)—, —O—SO₂—NR^(A)—, —NR^(A)—SO₂—O—,—NR^(A)—C(O)—NR^(B)—, —NR^(A)—C(S)—NR^(B)— and —NR^(A)—SO₂—NR^(B)—;

wherein each R^(A) and R^(B) is independently selected from the groupconsisting of hydrogen, C₁₋₈alkyl, hydroxy substituted C₁₋₄alkyl,C₁₋₄aralkyloxy substituted C₁₋₄alkyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl,heteroaryl-C₁₋₄alkyl-, heterocycloalkyl-C₁₋₄alkyl- andspiro-heterocyclyl;

wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl, whether alone or as part of a substituent group isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy-carbonyl, nitro, cyano, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, —SO₂—N(R^(C)R^(D)), 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one);

wherein each R^(C) and R^(D) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

R² is selected from the group consisting of C₁₋₁₀alkyl, cycloalkyl,aryl, biphenyl, partially unsaturated carbocyclyl, heteroaryl,heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl, partiallyunsaturated carbocyclyl-C₁₋₄alkyl-, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl;

wherein the C₁₋₁₀alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkylor spiro-heterocyclyl, whether alone or as part of a substituent groupis optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,—C(O)—C₁₋₄alkyl, —C(O)—C₁₋₄aralkyl, —C(O)O—C₁₋₄alkyl,—C(O)O—C₁₋₄aralkyl, —C₁₋₄alkyl-C(O)O—C₁₋₄alkyl, —C₁₋₄alkyl-S—C₁₋₄alkyl,—C(O)—N(R^(L)R^(M)), —C₁₋₄alkyl-C(O)—N(R^(L)R^(M)),—NR^(L)—C(O)—C₁₋₄alkyl, —SO₂—N(R^(L)R^(M)),—C₁₋₄alkyl-SO₂—N(R^(L)R^(M)), C₁₋₆alkyl, fluoro substituted C₁₋₄alkyl,hydroxy substituted C₁₋₄alkyl, carboxy substituted C₁₋₄alkyl,C₁₋₄alkoxy, nitro, cyano, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,phenyl, 5-tetrazolyl and 1-(1,4-dihydro-tetrazol-5-one);

wherein the phenyl is optionally substituted with one or moresubstituent independently selected from the group consisting of halogen,hydroxy, oxo, carboxy, —C(O)O—C₁₋₄alkyl, —C(O)—C₁₋₄alkyl, C₁₋₄alkyl,fluoro substituted C₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano, amino,C₁₋₄alkylamino and di(C₁₋₄alkyl)amino;

wherein each R^(L) and R^(M) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

b is an integer from 0 to 1;

L¹ is selected from the group consisting of —O—, —S(O)₀₋₂—, —NR^(N)—,—C(O)—, —C(S)—, —C₁₋₄alkyl-, -(hydroxy substituted C₁₋₄alkyl) and—(C₂₋₄alkenyl)-;

wherein R^(N) is selected from the group consisting of hydrogen andC₁₋₄alkyl;

R³ is selected from the group consisting of C₁₋₆alkyl, C₂₋₆alkenyl,cycloalkyl, partially unsaturated carbocyclyl, aryl, biphenyl,heteroaryl, heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl,heteroaryl-C₁₋₄alkyl-, heterocycloalkyl-C₁₋₄alkyl- andspiro-heterocyclyl;

wherein the C₁₋₆alkyl, cycloalkyl, partially unsaturated carbocyclyl,aryl, heteroaryl, heterocycloalkyl or spiro-heterocyclyl, whether aloneor as part of a substituent group is optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, hydroxy, oxo, carboxy, C₁₋₄alkyl, hydroxy substitutedC₁₋₄alkyl, halogen substituted C₁₋₄alkyl, cyano substituted C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, halogen substituted C₁₋₄alkoxy,nitro, cyano, —R⁵, —O—R⁵, —S—R⁵, —SO₂—R⁵, —SO₂—NR^(P)—R⁵,—NR^(P)—SO₂—R⁵, —NH₂, —N(R^(P))—R⁵, —C(O)—R⁵, —C(O)—NH₂,—C(O)—NR^(P)—R⁵, —NR^(P)—C(O)—R⁵ and —NR^(P)—C(O)O—R⁵;

wherein R⁵ is selected from the group consisting of C₁₋₄alkyl, aryl,C₁₋₄aralkyl, partially unsaturated carbocyclyl, cycloalkyl,cycloalkyl-C₁₋₄alkyl-, partially unsaturated carbocyclyl-C₁₋₄alkyl-,heteroaryl, heteroaryl-C₁₋₄alkyl-, heterocycloalkyl andheterocyclyl-C₁₋₄alkyl-;

wherein the aryl, C₁₋₄aralkyl, partially unsaturated carbocyclyl,cycloalkyl, heteroaryl or heterocycloalkyl, whether alone or as part ofa substituent group may be optionally substituted with one or moresubstituent independently selected from the group consisting ofC₁₋₄alkyl, C₁₋₄alkoxy, halogen, hydroxy, carboxy, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, cyano and nitro;

wherein R^(P) is selected from the group consisting of hydrogen,C₁₋₈alkyl, hydroxy substituted C₁₋₄alkyl, C₁₋₄aralkyloxy substitutedC₁₋₄alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl,cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl;

wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl, whether alone or as part of a substituent group isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy-carbonyl, nitro, cyano, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, —SO₂—N(R^(S)R^(T)), 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one);

wherein each R^(S) and R^(T) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

a is an integer from 0 to 3;

each R¹⁰ is independently selected from the group consisting of hydroxy,halogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogenated C₁₋₄alkyl, halogenatedC₁₋₄alkoxy, —C(O)—NR^(V)R^(W), —SO₂—NR^(V)R^(W), —C(O)—C₁₋₄alkyl and—SO₂—C₁₋₄alkyl;

wherein each R^(V) and R^(W) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl; alternatively R^(V) and R^(W) aretaken together with the N atom to which they are bound to form a 5 to 6membered saturated, partially unsaturated or aromatic ring structure;

provided that the halogens on the halogenated C₁₋₄alkyl or thehalogenated C₁₋₄alkoxy are selected from chloro or fluoro;

provided that when R⁰ is hydrogen, R¹ is hydrogen, b is 1, L¹ is —O—, R³is C₃alkyl, wherein the C₃alkyl is substituted with —C(O)—NR^(P)—R⁵wherein R^(P) is methyl and R⁵ is cyclohexyl, A¹ is —CH₂—, Q¹ is—C(O)—O— then R² is other than C₁₋₆alkyl, cycloalkyl or C₁₋₄aralkyl;

provided further that when R⁰ is hydrogen, R¹ is hydrogen, b is 1, L¹ is—O—, R³ is C₃alkyl, wherein the C₃alkyl is substituted with—C(O)—NR^(P)—R⁵ wherein R^(P) is methyl and R⁵ is cyclohexyl, A¹ is—CH₂—, Q¹ is —C(O)— then R² is other than morpholinyl or piperidinyl;

provided further that when R⁰ is hydrogen, R¹ is hydrogen, b is 1, L¹ is—O—, R³ is C₃alkyl, wherein the C₃alkyl is substituted with—C(O)—NR^(P)—R⁵ wherein R^(P) is methyl and R⁵ is cyclohexyl, A¹ is—CH₂—, Q¹ is —C(O)—NH— then R² is other than phenyl;

and pharmaceutically acceptable salts thereof.

In an embodiment, the present invention is directed to compounds offormula (II)

wherein

R⁰ is selected from the group consisting of hydrogen, methyl, and CF₃;

R¹ is selected from the group consisting of hydrogen, hydroxy, methyl,ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy andmethyl-carbonyl;

c is an integer from 0 to 1;

A² is selected from C₁₋₄alkyl; wherein the C₁₋₄alkyl is optionallysubstituted with one or more R^(Y) substituents;

wherein each R^(Y) is independently selected from the group consistingof hydroxy, oxo, C₁₋₄alkyl, C₁₋₄alkoxy, hydroxy substituted C₁₋₄alkyl,amino substituted C₁₋₆alkyl, cycloalkyl, cycloalkyl-C₁₋₄alkyl-,biphenyl, aryl, C₁₋₄aralkyl, heteroaryl, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl, heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl;

wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl group, whether alone or as part of a substituentgroup is optionally substituted with a substituent selected from thegroup consisting of fluoro, chloro, hydroxy, oxo, carboxy, C₁₋₄alkyl,C₁₋₄alkoxy, —C(O)—(C₁₋₄alkoxy), hydroxy substituted C₁₋₄alkyl, fluorosubstituted C₁₋₄alkyl, fluoro substituted C₁₋₄alkoxy, 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one);

is selected from the group consisting of aryl, aryl-C₁₋₄alkyl,cycloalkyl, partially unsaturated carbocyclyl, heteroaryl,heterocycloalkyl and spiro-heterocyclyl;

wherein the aryl, cycloalkyl, partially unsaturated carbocyclyl,heteroaryl, heterocycloalkyl or spiro-heterocyclyl group is optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, halogen substitutedC₁₋₄alkyl, halogen substituted C₁₋₄alkoxy, hydroxy substitutedC₁₋₄alkyl, hydroxy, carboxy, cyano, nitro, amino, C₁₋₄alkylamino anddi(C₁₋₄alkyl)amino;

provided that when c is 0 (i.e. A¹ is absent), then

is other than aryl or heteroaryl;

Q³ is selected from the group consisting of —O—, —S—, —C(O)—, —C(S)—,—C(O)O—, —OC(O)—, —C(O)—NR^(A)—, —NR^(A)—C(O)—, —C(S)—NR^(A),—SO₂—NR^(A)—, —SO—NR^(A), —OC(O)—NR^(A)—, —NR^(A)—C(O)O— and—O—SO₂—NR^(A)—;

wherein each R^(A) is independently selected from the group consistingof hydrogen, C₁₋₈alkyl, hydroxy substituted C₁₋₄alkyl, C₁₋₄aralkyloxysubstituted C₁₋₄alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl,cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl;

wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl, whether alone or as part of a substituent group isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy-carbonyl-, nitro, cyano, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, —SO₂—N(R^(C)R^(D)), 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one);

wherein each R^(C) and R^(D) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

R² is selected from the group consisting of C₁₋₁₀alkyl, cycloalkyl,aryl, biphenyl, partially unsaturated carbocyclyl, heteroaryl,heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl, partiallyunsaturated carbocyclyl-C₁₋₄alkyl-, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl;

wherein the C₁₋₁₀alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkylor spiro-heterocyclyl, whether alone or as part of a substituent groupis optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,—C(O)—C₁₋₄alkyl, —C(O)—C₁₋₄aralkyl, —C(O)O—C₁₋₄alkyl,—C(O)O—C₁₋₄aralkyl, —C₁₋₄alkyl-C(O)O—C₁₋₄alkyl, —C₁₋₄alkyl-S—C₁₋₄alkyl,—C(O)—N(R^(L)R^(M)), —C₁₋₄alkyl-C(O)—N(R^(L)R^(M)),—NR^(L)—C(O)O—C₁₋₄alkyl, —SO₂—N(R^(L)R^(M)),—C₁₋₄alkyl-SO₂—N(R^(L)R^(M)), C₁₋₆alkyl, fluoro substituted C₁₋₄alkyl,hydroxy substituted C₁₋₄alkyl, carboxy substituted C₁₋₄alkyl,C₁₋₄alkoxy, nitro, cyano, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,phenyl, 5-tetrazolyl and 1-(1,4-dihydro-tetrazol-5-one);

wherein the phenyl is optionally substituted with one or moresubstituent independently selected from the group consisting of halogen,hydroxy, oxo, carboxy, C(O)O—C₁₋₄alkyl, C(O)—C₁₋₄alkyl, C₁₋₄alkyl,fluoro substituted C₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano, amino,C₁₋₄alkylamino and di(C₁₋₄alkyl)amino;

wherein each R^(L) and R^(M) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

b is an integer from 0 to 1;

L¹ is selected from the group consisting of —O—, —S(O)₀₋₂—, —NR^(N)—,—C(O)—, —C(S)—, —C₁₋₄alkyl-, -(hydroxy substituted C₁₋₄alkyl)- and—(C₂₋₄alkenyl)-;

wherein R^(N) is selected from the group consisting of hydrogen andC₁₋₄alkyl;

R³ is selected from the group consisting of C₁₋₆alkyl, C₂₋₆alkenyl,cycloalkyl, partially unsaturated carbocyclyl, aryl, biphenyl,heteroaryl, heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl,heteroaryl-C₁₋₄alkyl-, heterocycloalkyl-C₁₋₄alkyl- andspiro-heterocyclyl;

wherein the C₁₋₆alkyl, cycloalkyl, partially unsaturated carbocyclyl,aryl, heteroaryl, heterocycloalkyl or spiro-heterocyclyl, whether aloneor as part of a substituent group is optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, hydroxy, oxo, carboxy, C₁₋₄alkyl, hydroxy substitutedC₁₋₄alkyl, halogen substituted C₁₋₄alkyl, cyano substituted C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, halogen substituted C₁₋₄alkoxy,nitro, cyano, —R⁵, —O—R⁵, —S—R⁵, —SO₂—R⁵, —SO₂—NR^(P)—R⁵,—NR^(A)—SO₂—R⁵, —NH₂, —N(R^(P))—R⁵, —C(O)—R⁵, —C(O)—NH₂,—C(O)—NR^(P)—R⁵, —NR^(P)—C(O)—R⁵ and —NR^(P)—C(O)O—R⁵;

wherein R⁵ is selected from the group consisting of C₁₋₄alkyl, aryl,C₁₋₄aralkyl, partially unsaturated carbocyclyl, cycloalkyl,cycloalkyl-C₁₋₄alkyl-, partially unsaturated carbocyclyl-C₁₋₄alkyl-,heteroaryl, heteroaryl-C₁₋₄alkyl-, heterocycloalkyl andheterocyclyl-C₁₋₄alkyl-;

wherein the aryl, C₁₋₄aralkyl, partially unsaturated carbocyclyl,cycloalkyl, heteroaryl or heterocycloalkyl, whether alone or as part ofa substituent group may be optionally substituted with one or moresubstituent independently selected from the group consisting ofC₁₋₄alkyl, C₁₋₄alkoxy, halogen, hydroxy, carboxy, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, cyano and nitro;

wherein R^(P) is selected from the group consisting of hydrogen,C₁₋₈alkyl, hydroxy substituted C₁₋₄alkyl, C₁₋₄aralkyloxy substitutedC₁₋₄alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl,cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl;

wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl, whether alone or as part of a substituent group isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy-carbonyl, nitro, cyano, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, —SO₂—N(R^(S)R^(T)), 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one);

wherein each R^(S) and R^(T) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

a is an integer form 0 to 3;

each R¹⁰ is independently selected from the group consisting of hydroxy,halogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogenated C₁₋₄alkyl, halogenatedC₁₋₄alkoxy, —C(O)—NR^(V)R^(W), —SO₂—NR^(V)R^(W), —C(O)—C₁₋₄alkyl and—SO₂—C₁₋₄alkyl;

wherein each R^(V) and R^(W) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl; alternatively R^(V) and R^(W) aretaken together with the N atom to which they are bound to form a 5 to 6membered saturated, partially unsaturated or aromatic ring structure;

provided that the halogens on the halogenated C₁₋₄alkyl and thehalogenated C₁₋₄alkoxy are selected from chloro or fluoro;

provided that when R⁰ is hydrogen, R¹ is hydrogen, A¹ is —CH₂—,

is phenyl, Q³ is —O—, R² is methyl, b is an integer selected from 0 to 1and L¹ is selected from —O—, —NH— or —N(CH₃)—, then R³ is other thanmethyl;

and pharmaceutically acceptable salts thereof.

In an embodiment, the present invention is directed to compounds offormula (I-AA)

wherein A¹, R^(A), R², b, L¹ and R³ are as herein defined. Preferably,in the compound of formula (I-AA), the A¹ group is substituted at thecarbon atom bound to nitrogen atom of the quinazoline core (i.e. at thealpha carbon atom).

In another embodiment, the present invention is directed to compounds offormula (I-BB)

wherein A¹, R^(A) and R² are as herein defined. Preferably, in thecompound of formula (I-BB), the A¹ group is substituted at the carbonatom bound to nitrogen atom of the quinazoline core (i.e. at the alphacarbon atom).

In an embodiment, the present invention is directed to compounds offormula (II-AA)

wherein R³, Q³ and R² are as herein defined.

In an embodiment of the present invention are compounds of formula (I)wherein the -(L¹)_(b)-R³ substituent group is bound at the 6 or 7position, preferably at the 6-position. In another embodiment of thepresent invention, are compounds of formula (II) wherein -Q³-R²substituent group is bound at the 2-, 3-, 4- or 5-position of the

substituent, perferably at the 3-position of the

substituent.

In an embodiment of the present invention is a compound of formula (III)wherein the -(L²)_(d)-R⁷-L³-R⁸ substituent group is bound at the 6 or 7position, preferably at the 6-position. In another embodiment of thepresent invention, is a compound of formula (III) wherein the -L³-R⁸substituent group is bound at the 2-, 3- or 4-position of the R⁷substituent, preferably, at the 3-position of the R⁷ substituent.

In an embodiment of the present invention, R⁰ is selected from the groupconsisting of hydrogen and methyl. In another embodiment of the presentinvention, R⁰ is hydrogen.

In an embodiment of the present invention, R¹ is selected from the groupconsisting of hydrogen, hydroxy, methyl, trifluoromethyl, methoxy andmethyl-carbonyl. In another embodiment of the present invention R¹ isselected from the group consisting of hydrogen, hydroxy and methoxy. Inyet another embodiment of the present invention, R¹ is hydrogen.

In an embodiment of the present invention, A¹ is selected from the groupconsisting of C₁₋₄alkyl; wherein the C₁₋₄alkyl is optionally substitutedwith one to two R^(X) substituents; wherein each R^(X) is independentlyselected from hydroxy, oxo, C₁₋₈alkyl, C₁₋₈alkoxy, hydroxy substitutedC₁₋₄alkyl, cycloalkyl, cycloalkyl-C₁₋₄alkyl, biphenyl, aryl,C₁₋₄aralkyl, heteroaryl, heteroaryl-C₁₋₄alkyl-, heterocycloalkyl,heterocycloalkyl-C₁₋₄alkyl-, spiro-heterocyclyl and—(C₁₋₄alkyl)_(n)-Q²-R⁴; and wherein the cycloalkyl, aryl, heteroaryl orheterocycloalkyl group, whether alone or as part of a substituent groupis optionally substituted with fluoro, chloro, hydroxy, oxo, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, hydroxy substituted C₁₋₄alkyl, fluoro substitutedC₁₋₄alkyl, fluoro substituted C₁₋₄alkoxy, 5-tetrazolyl or1-(1,4-dihydro-tetrazol-5-one).

In another embodiment of the present invention, A¹ is selected from thegroup consisting of C₁₋₄alkyl; wherein the C₁₋₄alkyl is optionallysubstituted with one to two R^(X) substituents; wherein each R^(X) isindependently selected from the group consisting of C₁₋₈alkyl, hydroxysubstituted C₁₋₄alkyl, cycloalkyl, aryl, C₁₋₄aralkyl, biphenyl,heterocycloalkyl, spiro-heterocyclyl and —(C₁₋₄alkyl)_(n)-Q²-R⁴; whereinthe cycloalkyl, aryl, whether alone or as part of a substituent group isoptionally substituted with fluoro, chloro, hydroxy, oxo, C₁₋₄alkyl orC₁₋₄alkoxy.

In another embodiment of the present invention, A¹ is selected from thegroup consisting of methyl, ethyl, 1-methyl-ethyl, (1)-(R)-methyl-ethyl,(1)-(S)-methyl-ethyl, 1-n-propyl-ethyl, (1)-(R)-n-propyl-ethyl,(1)-(S)-n-propyl-ethyl, 1-isopropyl-ethyl, (1)-(R)-isopropyl-ethyl,(1)-(S)-isopropyl-ethyl, 1-cyclohexyl-ethyl, (1)-(R)-cyclohexyl-ethyl,(1)-(S)-cyclohexyl-ethyl, 1-phenyl-ethyl, 1-(4-hydroxybenzyl)-ethyl,(1)-(R)-(4-hydroxybenzyl)-ethyl, (1)-(S)-(4-hydroxybenzyl)-ethyl,1-(1-carboxy-2-hydroxy-ethyl), 1-(S)-(1-carboxy-2-hydroxy-ethyl),1-(R)-(1-carboxy-2-hydroxy-ethyl), 1-(1-carboxy-2-t-butoxy-ethyl),1-(R)-(1-carboxy-2-t-butoxy-ethyl), 1-(1-carboxy-2-benzyloxy-ethyl),1-(S)-(1-carboxy-2-benzyloxy-ethyl),1-(R)-(1-carboxy-2-benzyloxy-ethyl),1-(1-methoxy-carbonyl-2-benzyloxy-ethyl),1-(S)-(1-methoxy-carbonyl-2-benzyloxy-ethyl),1-(R)-(1-methoxy-carbonyl-2-benzyloxy-ethyl), n-propyl,1-hydroxymethyl-n-propyl, (1)-(R)-hydroxymethyl-n-propyl,(1)-(S)-hydroxymethyl-n-propyl, 1-(dimethyl)-n-propyl,1-(n-propyl)-n-propyl, 1-isopropyl-n-propyl, (1)-(S)-isopropyl-n-propyl,(1)-(R)-isopropyl-n-propyl, 1-(n-pentyl)-n-propyl, 1-n-octyl-n-propyl,1-cyclohexyl-n-propyl, (1)-(R)-cyclohexyl-n-propyl,(1)-(S)-cyclohexyl-n-propyl, 1-phenyl-n-propyl,1-(4-chlorophenyl)-n-propyl, 1-(4-methylphenyl)-n-propyl,1-(4-methoxyphenyl)-n-propyl, 1-(4-biphenyl)-n-propyl,1-(N-piperidiny-carbonyl-n-propyl)-n-propyl,1-(4-tetrahydropyranyl)-n-propyl,(1)-(R)-(4-tetrahydropyranyl)-n-propyl,(1)-(S)-(4-tetrahydropyranyl)-n-propyl,1-(4-hydroxy-cyclohexyl)-n-propyl,1-(N-methyl-N-cyclohexyl-aminocarbonyl)-n-propyl,(1)-(R)-(N-methyl-N-cyclohexyl-aminocarbonyl)-n-propyl,(1)-(S)-(N-methyl-N-cyclohexyl-aminocarbonyl)-n-propyl,1-(1,4-dioxaspiro[4.5]decane)-n-propyl,(1)-(R)-(1,4-dioxaspiro[4.5]decane)-n-propyl,(1)-(S)-(1,4-dioxaspiro[4.5]dec-8-yl)-n-propyl,(1)-(R)-((4R)-hydroxycyclohexyl)-n-propyl,1-(cylcohexan-4-one)-n-propyl, (1)-(R)-(cylcohexan-4-one)-n-propyl,(1)-(S)-(cylcohexan-4-one)-n-propyl, 1-pyranyl-n-propyl,(1)-(S)-pyranyl-n-propyl, n-butyl, 1-propyl-n-butyl, 1-phenyl-n-butyl,1-(cyclohexylcarbonylaminomethyl)-ethyl,1-(N-cyclohexyl-N-methyl-aminocarbonylethyl)-n-propyl,1-(2-methyl-piperidinylcarbonyl-n-propyl)-n-propyl and1-(4-methyl-piperidinylcarbonyl-n-propyl)-n-propyl.

In another embodiment of the present invention, A¹ is selected from thegroup consisting of methyl, ethyl, 1-methyl-ethyl, (1)-(R)-methyl-ethyl,(1)-(S)-methyl-ethyl, 1-n-propyl-ethyl, (1)-(R)-n-propyl-ethyl,(1)-(S)-n-propyl-ethyl, 1-isopropyl-ethyl, (1)-(R)-isopropyl-ethyl,(1)-(S)-isopropyl-ethyl, 1-cyclohexyl-ethyl, (1)-(R)-cyclohexyl-ethyl,(1)-(S)-cyclohexyl-ethyl, 1-phenyl-ethyl, 1-(4-hydroxybenzyl)-ethyl,(1)-(R)-(4-hydroxybenzyl)-ethyl, (1)-(S)-(4-hydroxybenzyl)-ethyl,n-propyl, 1-hydroxymethyl-n-propyl, (1)-(R)-hydroxymethyl-n-propyl,(1)-(S)-hydroxymethyl-n-propyl, 1-(dimethyl)-n-propyl,1-(n-propyl)-n-propyl, 1-isopropyl-n-propyl, (1)-(S)-isopropyl-n-propyl,(1)-(R)-isopropyl-n-propyl, 1-(n-pentyl)-n-propyl, 1-n-octyl-n-propyl,1-cyclohexyl-n-propyl, (1)-(R)-cyclohexyl-n-propyl,(1)-(S)-cyclohexyl-n-propyl, 1-phenyl-n-propyl,1-(4-chlorophenyl)-n-propyl, 1-(4-methylphenyl)-n-propyl,1-(4-methoxyphenyl)-n-propyl, 1-(4-biphenyl)-n-propyl,1-(N-piperidiny-carbonyl-n-propyl)-n-propyl,1-(4-tetrahydropyranyl)-n-propyl,(1)-(R)-(4-tetrahydropyranyl)-n-propyl,(1)-(S)-(4-tetrahydropyranyl)-n-propyl,1-(4-hydroxy-cyclohexyl)-n-propyl,1-(N-methyl-N-cyclohexyl-aminocarbonyl)-n-propyl,(1)-(R)-(N-methyl-N-cyclohexyl-aminocarbonyl)-n-propyl,(1)-(S)-(N-methyl-N-cyclohexyl-aminocarbonyl)-n-propyl,1-(1,4-dioxaspiro[4.5]decane)-n-propyl,(1)-(R)-(1,4-dioxaspiro[4.5]decane)-n-propyl,(1)-(S)-(1,4-dioxaspiro[4.5]dec-8-yl)-n-propyl,(1)-(R)-((4R)-hydroxycyclohexyl)-n-propyl,1-(cylcohexan-4-one)-n-propyl, (1)-(R)-(cylcohexan-4-one)-n-propyl,(1)-(S)-(cylcohexan-4-one)-n-propyl, 1-pyranyl-n-propyl,(1)-(S)-pyranyl-n-propyl, n-butyl, 1-propyl-n-butyl, 1-phenyl-n-butyl,1-(cyclohexylcarbonylaminomethyl)-ethyl,1-(N-cyclohexyl-N-methyl-aminocarbonylethyl)-n-propyl,1-(2-methyl-piperidinylcarbonyl-n-propyl)-n-propyl and1-(4-methyl-piperidinylcarbonyl-n-propyl)-n-propyl.

In an embodiment of the present invention, A¹ is selected from the groupconsisting of -ethyl-, -n-butyl-, -n-propyl-, 1-(R)-methyl-ethyl-,1-n-propyl-ethyl-, 1-cyclohexyl-ethyl-, 1-(R)-cyclohexyl-ethyl-,1-cyclohexyl-n-propyl, 1-(S)-cyclohexyl-n-propyl,1-(R)-cyclohexyl-n-propyl, 1-(n-propyl)-n-propyl, 1-(n-propyl)-n-butyl-,1-(R)-isopropyl-n-propyl, 1-(S)-isopropyl-n-propyl,1-(4-chlorophenyl)-n-propyl, 1-(4methylphenyl)-n-propyl,1-(4-methoxyphenyl)-n-propyl, 1-(phenyl)-ethyl-,1-(cyclohexyl-carbonyl-amino-methyl)-ethyl and1-(N-cyclohexyl-N-methyl-amino-carbonyl-ethyl)-n-propyl.

In another embodiment of the present invention, A¹ is selected from thegroup consisting of -ethyl-, -n-butyl-, 1-(R)-methyl-ethyl-,1-n-propyl-ethyl-, 1-cyclohexyl-ethyl-, 1-(R)-cyclohexyl-ethyl-,1-cyclohexyl-n-propyl, 1-(S)-cyclohexyl-n-propyl, 1-(n-propyl)-n-propyl,1-(n-propyl)-n-butyl-, 1-(R)-isopropyl-n-propyl,1-(S)-isopropyl-n-propyl, 1-(4-chlorophenyl)-n-propyl,1-(4methylphenyl)-n-propyl and 1-(4-methoxyphenyl)-n-propyl.

In another embodiment of the present invention, A¹ is selected from thegroup consisting of -ethyl-, 1-n-propyl-ethyl-, 1-cyclohexyl-ethyl-,1-(R)-cyclohexyl-ethyl-, 1-cyclohexyl-n-propyl,1-(S)-cyclohexyl-n-propyl, 1-(n-propyl)-n-propyl,1-(R)-isopropyl-n-propyl and 1-(S)-isopropyl-n-propyl.

In another embodiment of the present invention, A¹ is selected from thegroup consisting of -ethyl-, -n-butyl-, -n-propyl-, 1-(R)-methyl-ethyl,1-n-propyl-ethyl, 1-(R)-n-propyl-ethyl-, 1-(n-propyl)-n-propyl-,1-(n-propyl)-n-butyl-, 1-isopropyl-ethyl-, 1-(n-pentyl)-n-propyl-,1-cyclohexyl-ethyl-, 1-(R)-cyclohexyl-ethyl, 1-(S)-cyclohexyl-ethyl,1-phenyl-ethyl, 1-(4-chlorophenyl)-n-propyl-,1-(4-methoxyphenyl)-n-propyl, 1-cyclohexyl-n-propyl-,1-phenyl-n-propyl-, 1-(R)-isopropyl-n-propyl, 1-(S)-isopropyl-n-propyl,1-(R)-cyclohexyl-n-propyl-, 1-(S)-(cyclohexyl)-n-propyl-,1-(S)-(hydroxymethyl)-n-propyl-, 1-(4-tetrahydropyranyl)-n-propyl-,1-(S)-(4-tetrahydropyranyl)-n-propyl-,1-(4-hydroxy-cyclohexyl)-n-propyl-, 1-(S)-(4-oxo-cyclohexyl)-n-propyl,1-(S)-(cis-4-hydroxy-cyclohexyl)-n-propyl,1-(S)-(N-cyclohexyl-N-methyl-amino-carbonyl)-n-propyl-,1-(N-cyclohexyl-N-methyl-amino-carbonyl-ethyl)-n-propyl- and1-(S)-(1,4-dioxa-spiro[4.5]dec-8-yl)-n-propyl.

In another embodiment of the present invention, A¹ is selected from thegroup consisting of -ethyl-, -n-propyl-, 1-(R)-methyl-ethyl,1-n-propyl-ethyl, 1-(R)-n-propyl-ethyl-, 1-(n-propyl)-n-propyl-,1-(n-propyl)-n-butyl-, 1-(n-pentyl)-n-propyl-, 1-cyclohexyl-ethyl-,1-(R)-cyclohexyl-ethyl, 1-phenyl-ethyl, 1-(4-chlorophenyl)-n-propyl-,1-(4-methoxyphenyl)-n-propyl, 1-cyclohexyl-n-propyl-,1-phenyl-n-propyl-, 1-(R)-isopropyl-n-propyl, 1-(S)-isopropyl-n-propyl,1-(R)-cyclohexyl-n-propyl-, 1-(S)-(cyclohexyl)-n-propyl-,1-(S)-hydroxymethyl)-n-propyl-, 1-(4-tetrahydropyranyl)-n-propyl-,1-(S)-(4-tetrahydropyranyl)-n-propyl-,1-(4-hydroxy-cyclohexyl)-n-propyl-, 1-(S)-(4-oxo-cyclohexyl)-n-propyl,1-(S)-(cis-4-hydroxy-cyclohexyl)-n-propyl,1-(S)-(N-cyclohexyl-N-methyl-amino-carbonyl)-n-propyl- and1-(S)-(1,4-dioxa-spiro[4.5]dec-8-yl)-n-propyl.

In another embodiment of the present invention, A¹ is selected from thegroup consisting of -ethyl-, 1-cyclohexyl-ethyl-,1-(R)-cyclohexyl-ethyl, 1-cyclohexyl-n-propyl-,1-(R)-isopropyl-n-propyl, 1-(S)-isopropyl-n-propyl,1-(R)-cyclohexyl-n-propyl-, 1-(S)-(cyclohexyl)-n-propyl-,1-(4-tetrahydropyranyl)-n-propyl-,1-(S)-(4-tetrahydropyranyl)-n-propyl-,1-(4-hydroxy-cyclohexyl)-n-propyl- and1-(S)-(4-oxo-cyclohexyl)-n-propyl.

In an embodiment of the present invention, Q² is selected from the groupconsisting of —O—, —C(O)—, —C(O)O—, —OC(O)—, —NR^(G)—, —NR^(G)—C(O)— and—C(O)—NR^(G)—; wherein R^(G) is selected from the group consisting ofhydrogen, C₁₋₈alkyl, hydroxy substituted C₁₋₄alkyl, C₁₋₄aralkyloxysubstituted C₁₋₄alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyland C₁₋₄aralkyl; wherein the cycloalkyl, aryl, heteroaryl,heterocycloalkyl or spiro-heterocyclyl, whether alone or as part of asubstituent group is optionally substituted with one to two substituentsindependently selected from halogen, hydroxy, oxo, carboxy, C₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄alkoxy-carbonyl, nitro, cyano, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —SO₂—N(R^(J)R^(K), 5-tetrazolyl or1-(1,4-dihydro-tetrazol-5-one); and wherein each R^(J) and R^(K) isindependently selected from hydrogen or C₁₋₄alkyl.

In another embodiment of the present invention, Q² is selected from thegroup consisting of —C(O)—, —C(O)—NR^(G)— and —NR^(G)—C(O)—; whereinR^(G) is selected from the group consisting of hydrogen and C₁₋₄alkyl.

In a embodiment of the present invention, R⁴ is selected from the groupconsisting of C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, fluorosubstituted C₁₋₄alkyl, cycloalkyl, aryl, biphenyl, heteroaryl,heterocycloalkyl and C₁₋₄aralkyl; wherein the cycloalkyl, aryl,heteroaryl or heterocycloalkyl, whether alone or as part of asubstituent group is optionally substituted with one to two substituentsindependently selected from halogen, hydroxy, oxo, carboxy,C(O)O—C₁₋₄alkyl, C(O)—C₁₋₄alkyl, C₁₋₄alkyl, fluoro substitutedC₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino or phenyl; wherein the phenyl is optionallysubstituted with one to two substituent independently selected fromhalogen, hydroxy, oxo, carboxy, —C(O)O—C₁₋₄alkyl, —C(O)—C₁₋₄alkyl,C₁₋₄alkyl, fluoro substituted C₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano,amino, C₁₋₄alkylamino and di(C₁₋₄alkyl)amino.

In another embodiment of the present invention, R⁴ is selected from thegroup consisting of cycloalkyl and heterocycloalkyl.

In an embodiment of the present invention, Q¹ is selected from the groupconsisting of —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —OC(O)—, —C(O)—NH—,—C(O)—N(CH₃)—, —C(O)—N(CH₂CH₃)—, —C(O)—N(CH₂CH₂OH)—,—C(O)—N(C₁₋₄alkyl))-, —C(O)—N(cycloalkyl)-,—C(O)—N(CH₂CH₂—O—C₁₋₄aralkyl)-, —NH—, —N(C₁₋₄alkyl)-, —NH-C(O)—,—N(C₁₋₄alkyl)-C(O)—, —NH—C(O)O—, —N(C₁₋₄alkyl)—C(O)O—, —NH—SO₂—,—SO₂—NH—, —NH—C(O)—NH—, NH—C(S)—NH— and —NH—SO₂—NH—.

In another embodiment of the present invention, Q¹ is selected from thegroup consisting of —O—, —C(O)—, —C(O)O—, —C(O)—NH—, —C(O)—N(CH₃)—,—C(O)—N(CH₂CH₃)—, —C(O)—N(CH₂CH₂OH)—, —C(O)—N(C₁₋₄alkyl))-,—C(O)—N(cycloalkyl)-, —C(O)—N(CH₂CH₂—O—C₁₋₄aralkyl)-, —NH—,—N(C₁₋₄alkyl)-, —NH—C(O)—, —N(C₁₋₄alkyl)-C(O)—, —NH—C(O)O—,—N(C₁₋₄alkyl)-C(O)O—, —NH—SO₂—, —NH—C(O)—NH— and NH—C(S)—NH—.

In another embodiment of the present invention, Q¹ is selected from thegroup consisting of —O—, —C(O)—, —C(O)O—, —C(O)—NH—, —C(O)—N(CH₃)—,—C(O)—N(CH₂CH₃)—, —C(O)—N(CH₂CH₂OH)—, —C(O)—N(isopropyl)-,—C(O)—N(cyclohexyl)-, —C(O)—N(CH₂CH₂—O-benzyl)-, —NH—, —N(CH₃)—,—N(CH₂CH₃)—, —NH—C(O)—, —N(CH₃)—C(O)—, —NH—C(O)O—, —N(CH₃)—C(O)O—,—NH—SO₂—, —NH—C(O)—NH— and NH—C(S)—NH—.

In an embodiment of the present invention, Q¹ is selected from the groupconsisting of —C(O)—NH—, —C(O)—N(CH₃)—, —C(O)—N(cyclohexyl)-, —NH—C(O)—,—NH—C(O)O—, —N(CH₃)—C(O)O—, —NH—C(O)—NH—, —NH—C(S)—NH and —NH—SO₂—. Inanother embodiment of the present invention, Q¹ is selected from thegroup consisting of —C(O)—NH—, —C(O)—N(CH₃)—, —C(O)—N(cyclohexyl)-,—NH—C(O)—, —NH—C(O)O—, —N(CH₃)—C(O)O—, —NH—C(O)—NH— and —NH—C(S)—NH. Inyet another embodiment of the present invention, Q¹ is selected from thegroup consisting of —C(O)—NH—, —C(O)—N(CH₃)— and —NH—C(O)—.

In an embodiment of the present invention, Q¹ is selected from the groupconsisting of —C(O)—NH—, —C(O)—N(CH₃)—, —C(O)—N(ethyl)-,—C(O)—N(cyclohexyl)-, —C(O)—N(hydroxyethyl)-, —C(O)—N(benzyloxy-ethyl)-,—N(CH₃)—, —NH—C(O)—, —N(CH₃)—C(O)—, —NH—C(O)O—, —N(CH₃)—C(O)O—,—NH—C(O)—NH, —NH—C(S)—NH and —NH—SO₂—. In another embodiment of thepresent invention, Q¹ is selected from the group consisting of—C(O)—NH—, —C(O)—N(CH₃)—, —C(O)—N(ethyl)-, —C(O)—N(hydroxyethyl)-,—C(O)—N(benzyloxy-ethyl)-, —N(CH₃)—, —NH—C(O)—, —NH—C(O)O—,—N(CH₃)—C(O)O— and —NH—C(S)—NH. In yet another embodiment of the presentinvention, Q¹ is selected from the group consisting of —C(O)—NH—,—C(O)—N(CH₃)—, —C(O)—N(hydroxyethyl)-, —C(O)—N(benzyloxy-ethyl)- and—NH—C(O)—.

In another embodiment of the present invention, Q¹ is selected from thegroup consisting of —C(O)—NH—, —C(O)—N(CH₃)—, —C(O)—N(ethyl)-,—C(O)—N(CH₂CH₂OH)—, —C(O)—N(cyclohexyl)-, —C(O)—N(hydroxyethyl)-,—C(O)—N(benzyloxy-ethyl)-, —N(CH₃)—, —NH—C(O)—, —N(CH₃)—C(O)—,—NH—C(O)O—, —N(CH₃)—C(O)O—, —NH—C(O)—NH, —NH—C(S)—NH and —NH—SO₂—.

In another embodiment of the present invention, Q¹ is selected from thegroup consisting of —C(O)—NH—, —C(O)—N(CH₃)—, —C(O)—N(ethyl)-,—C(O)—N(CH₂CH₂OH)—, —C(O)—N(hydroxyethyl)-, —C(O)—N(benzyloxy-ethyl)-,—N(CH₃)—, —NH—C(O)—, —NH—C(O)O—, —N(CH₃)—C(O)O— and —NH—C(S)—NH.

In another embodiment of the present invention, Q¹ is selected from thegroup consisting of —C(O)—NH—, —C(O)—N(CH₃)—, —C(O)-N(hydroxyethyl)-,—C(O)—N(benzyloxy-ethyl)-, —C(O)-N(cyclohexyl)- and —NH—C(O)—.

In an embodiment of the present invention, R² is selected from the groupconsisting of C₁₋₁₀alkyl, cycloalkyl, aryl, biphenyl, partiallyunsaturated carbocyclyl, heteroaryl, heterocycloalkyl,cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl, partially unsaturatedcarbocyclyl-C₁₋₄alkyl-, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl;

wherein the C₁₋₁₀alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkylor spiro-heterocyclyl, whether alone or as part of a substituent groupis optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,—C(O)—C₁₋₄alkyl, —C(O)—C₁₋₄aralkyl, —C(O)O—C₁₋₄alkyl,—C(O)O—C₁₋₄aralkyl, —C₁₋₄alkyl-C(O)O—C₁₋₄alkyl, —C₁₋₄alkyl-S—C₁₋₄alkyl,—C(O)—N(R^(L)R^(M)), —C₁₋₄alkyl-C(O)—N(R^(L)R^(M)),—NR^(L)—C(O)—C₁₋₄alkyl, —SO₂—N(R^(L)R^(M)),—C₁₋₄alkyl-SO₂—N(R^(L)R^(M)), C₁₋₆alkyl, fluoro substituted C₁₋₄alkyl,hydroxy substituted C₁₋₄alkyl, carboxy substituted C₁₋₄alkyl,C₁₋₄alkoxy, nitro, cyano, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,phenyl, 5-tetrazolyl and 1-(1,4-dihydro-tetrazol-5-one);

wherein the phenyl is optionally substituted with one or moresubstituent independently selected from the group consisting of halogen,hydroxy, oxo, carboxy, C(O)O—C₁₋₄alkyl, C(O)—C₁₋₄alkyl, C₁₋₄alkyl,fluoro substituted C₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano, amino,C₁₋₄alkylamino and di(C₁₋₄alkyl)amino;

wherein each R^(L) and R^(M) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

In another embodiment of the present invention, R² is selected from thegroup consisting of C₁₋₁₀alkyl, cycloalkyl, aryl, biphenyl, partiallyunsaturated carbocyclyl, heteroaryl, heterocycloalkyl,cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl, partially unsaturatedcarbocyclyl-C₁₋₄alkyl-, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl;

wherein the C₁₋₁₀alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkylor spiro-heterocyclyl, whether alone or as part of a substituent groupis optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,—C(O)—C₁₋₄alkyl, —C(O)—C₁₋₄aralkyl, —C(O)O—C₁₋₄alkyl,—C(O)O—C₁₋₄aralkyl, —C(O)—N(R^(L)R^(M)), —C₁₋₄alkyl-C(O)O—C₁₋₄alkyl,—C₁₋₄alkyl-C(O)—N(R^(L)R^(M)), —NR^(L)—C(O)—C₁₋₄alkyl, C₁₋₆alkyl, fluorosubstituted C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, carboxysubstituted C₁₋₄alkyl, C₁₋₄alkoxy, —O—C₁₋₄aralkyl,—O-(tetrahydropyranyl), —NH—C(O)—O—CH₂-(tetrahydropyranyl), nitro,cyano, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino phenyl and5-tetrazolyl;

wherein the phenyl or tetrahydropyranyl is optionally substituted withone to two substituent independently selected from the group consistingof halogen, hydroxy, oxo, carboxy, —OC(O)—C₁₋₄alkyl,—C₁₋₄alkyl-OC(O)—C₁₋₄alkyl, C₁₋₄alkyl, fluoro substituted C₁₋₄alkyl,hydroxy substituted C₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano, amino,C₁₋₄alkylamino and di(C₁₋₄alkyl)amino;

wherein each R^(L) and R^(M) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl.

In another embodiment of the present invention, R² is selected from thegroup consisting of C₁₋₁₀alkyl, cycloalkyl, aryl, biphenyl, partiallyunsaturated carbocyclyl, heteroaryl, heterocycloalkyl,cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl, partially unsaturatedcarbocyclyl-C₁₋₄alkyl-, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl; wherein theC₁₋₁₀alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl, whether alone or as part of a substituent group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, oxo, carboxy, —C(O)—C₁₋₄alkyl,—C(O)—C₁₋₄aralkyl, —C(O)O—C₁₋₄alkyl, —C(O)O—C₁₋₄aralkyl,—C(O)—N(R^(L)R^(M)), —C₁₋₄alkyl-C(O)—N(R^(L)R^(M)),—NR^(L)—C(O)—C₁₋₄alkyl, C₁₋₆alkyl, fluoro substituted C₁₋₄alkyl, hydroxysubstituted C₁₋₄alkyl, carboxy substituted C₁₋₄alkyl, C₁₋₄alkoxy, nitro,cyano, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino or phenyl; wherein thephenyl is optionally substituted with one to two substituentindependently selected from halogen, hydroxy, oxo, carboxy, C₁₋₄alkyl,fluoro substituted C₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano, amino,C₁₋₄alkylamino or di(C₁₋₄alkyl)amino; and wherein each R^(L) and R^(M)is independently selected from the group consisting of hydrogen andC₁₋₄alkyl.

In another embodiment of the present invention, R² is selected from thegroup consisting of C₁₋₁₀alkyl, cycloalkyl, cycloalkyl-alkyl, aryl,C₁₋₄aralkyl, heteroaryl, heterocycloalkyl, spiro-heterocyclyl andheteroaryl-C₁₋₄alkyl-;

wherein the C₁₋₁₀alkyl, aryl, cycloalkyl, heteroaryl orheterocycloalkyl, whether alone or as part of a substituent group isoptionally substituted with one to two substituent independentlyselected from the group consisting of C₁₋₅alkyl, C₁₋₄alkoxy,—O—C₁₋₂aralkyl, —O-(tetrahydropyranyl),—NH—C(O)—O—CH₂-(tetrahydropyranyl), halogen, trifluoromethyl, amino,cyano, hydroxy, oxo, carboxy, phenyl, —C(O)—C₁₋₄alkyl,—C(O)O—C₁₋₂aralkyl, —C(O)—N(R^(L)R^(M)), —C(O)—N(C₁₋₄alkyl)(cycloalkyl),—NH—C(O)—C₁₋₄alkyl, —C(O)O—C₁₋₄alkyl, —C₁₂alkyl-C(O)O—C₁₋₄alkyl, carboxysubstituted C₁₋₂alkyl and 5-tetrazolyl;

wherein the phenyl or tetrahydropyranyl is optionally substituted withone to two substituents independently selected from the group consistingof hydroxy, halogen, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, hydroxy substitutedC₁₋₂alkyl, —OC(O)—C₁₋₂alkyl, —C₁₋₂alkyl-OC(O)—C₁₋₂alkyl, amino,C₁₋₄alkylamino and di(C₁₋₄alkyl)amino;

wherein R^(L) and R^(M) are each independently selected from the groupconsisting of hydrogen, methyl and ethyl.

In another embodiment of the present invention, R² is selected from thegroup consisting of C₁₋₁₀alkyl, cycloalkyl, cycloalkyl-alkyl, aryl,C₁₋₄aralkyl, heteroaryl, heterocycloalkyl and spiro-heterocyclyl;wherein the C₁₋₁₀alkyl, aryl, cycloalkyl, heteroaryl orheterocycloalkyl, whether alone or as part of a substituent group isoptionally substituted with one to two substituent independentlyselected from C₁₋₅alkyl, C₁₋₄alkoxy, halogen, trifluoromethyl, amino,cyano, hydroxy, oxo, carboxy, phenyl, —C(O)—C₁₋₄alkyl, —C(O)—NH₂,—C(O)—N(C₁₋₄alkyl)(cycloalkyl), —NH—C(O)—C₁₋₄alkyl or —C(O)O—C₁₋₄alkyl;wherein the phenyl is optionally substituted with one to twosubstituents independently selected from the group consisting ofhalogen, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, amino, C₁₋₄alkylamino anddi(C₁₋₄alkyl)amino.

In another embodiment of the present invention, R² is selected from thegroup consisting of methyl, ethyl, n-propyl, isopropyl, t-butyl,isobutyl, isopentyl, 3-n-heptyl, n-nonyl, amino-methyl, carboxy-methyl-,2-amino-ethyl, 2-cyano-ethyl, 4-carboxy-n-butyl, 3-n-heptyl, 4-n-heptyl,3-amino-n-propyl, 3,3,3-trifluoro-n-propyl, 3,3,3-trifluoro-isobutyl,1-(1-carboxy-2-hydroxy-ethyl), 1-(1-(S)-carboxy-2-hydroxy-ethyl),1-(1-(R)-carboxy-2-hydroxy-ethyl), 1-(1-carboxy-2-t-butoxy-ethyl),1-(1-(R)-carboxy-2-t-butoxy-ethyl), 1-(1-carboxy-2-benzyloxy-ethyl),1-(1-(S)-carboxy-2-benzyloxy-ethyl),1-(1-(R)-carboxy-2-benzyloxy-ethyl),1-(1-methoxy-carbonyl-2-benzyloxy-ethyl),1-(1-(S)-methoxy-carbonyl-2-benzyloxy-ethyl),1-(1-(R)-methoxy-carbonyl-2-benzyloxy-ethyl), cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, 2-phenyl-cyclopropyl,cyclopentyl-methyl, cyclopentyl-ethyl, 1-(1-aminocarbonyl-cyclopropyl),4-hydroxy-cyclohexyl, 4-carboxy-cyclohexyl, cis-(4-carboxy)-cyclohexyl,trans-(4-carboxy)-cyclohexyl, 3-carboxy-cyclohexyl,cis-(3-carboxy)-cyclohexyl, 4-cyano-cyclohexyl,4-methoxy-carbonyl-cyclohexyl, 3-methoxy-carbonyl-cyclohexyl,cis-(3-methoxy-carbonyl)-cyclohexyl, 4-ethoxy-carbonyl-cyclohexyl,(1)-(S)-((4R)-methoxy-carbonyl-cyclohexyl,(1)-(R)-((4S)-methoxy-carbonyl-cyclohexyl, 2-methyl-cyclohexyl,4-methyl-cyclohexyl, 4-n-pentyl-cyclohexyl, 4-t-butyl-cyclohexyl,(1)-(S)-2-(R)-methyl-cyclopentyl, 3-methoxy-cyclohexyl,1-(1-(4-chlorophenyl)-cyclopentyl), 4-trifluoromethyl-cyclohexyl,4-oxo-cyclohexyl, 1-(4-benzyloxy-carbonyl-cyclohexyl),1-(S)-(4-(S)-benzyloxy-carbonyl-cyclohexyl),1-(4-amino-carbonyl-cyclohexyl),1-(S)-(4-(S)-amino-carbonyl-cyclohexyl),1-(4-methylamino-carbonyl-cyclohexyl),1-(S)-(4-(S)-methylamino-carbonyl-cyclohexyl),1-(4-(5-tetrazolyl)-cyclohexyl), phenyl, benzyl, phenyl-ethyl,3-carboxy-methyl-benzyl, 3-methoxy-carbonyl-methyl-benzyl,4-carboxy-phenyl, 3-cyano-phenyl, 4-methyl-phenyl, 4-t-butyl-phenyl,4-n-butyl-phenyl, 2-methoxy-phenyl, 3-methoxy-phenyl,4-dimethylamino-phenyl, 4-(methylcarbonylamino)-phenyl,1-naphthyl-methyl, 1-(1,2,3,4-tetrahydro-naphthyl), 4-biphenyl,benzhydryl, 1-adamantyl, 2-adamantyl, 2-(R)-adamantyl, 2-(S)-adamantyl,N-piperidinyl, 1-(2-carboxy-piperidinyl), 1-(S)-2-carboxy-piperidinyl),1-(2-methoxy-carbonyl-piperidinyl),1-(S)-2-methoxy-carbonyl-piperidinyl), 1-(2-methyl-piperidinyl),1-(4-methyl-piperidinyl), 1-(4-isoproyl-piperidinyl),4-(1-methylcarbonyl)-piperidinyl), 3-(2,5-dimethyl-furyl),4-tetrahydropyranyl, 4-(2-phenyl-thiazolyl)-methyl,4-(1-phenyl-pyrazolyl)-methyl, 5-(3-methyl-isoxazolyl)-methyl,3-(5-phenyl-isoxazolyl)-methyl, 1-(2-carboxy-pyrrolidinyl),1-(S)-(2-carboxy-pyrrolidinyl),1-(2-(N-methyl-N-cyclohexylaminocarbonyl)-pyrrolidinyl),1,4-dioxaspiro[4.5]dec-8-yl, 2-(bicyclo[2.2.1 ]heptyl),1-(3-n-pentyl-bicyclo[2.2.2]-octyl, 2-bicyclo[2.2.2]octyl,2-(R)-bicyclo[2.2.2]octyl, 2-(S)-bicyclo[2.2.2]octyl,5-tetrazolyl-methyl, 2-imidazolyl-methyl, 5-imidazolyl-methyl,4-pyridyl-methyl, 3-(1,2,4-triazolyl)-methyl,1-(2-carboxy-octahydroindolyl), 1-(S)-(2-carboxy-octahydroindolyl),1-(2-methoxy-carbonyl-octahydroindolyl),1-(S)-2-methoxy-carbonyl-octahydroindolyl),2R-(3R,4S,5R-tri(methyl-carbonyloxy)-6R-(methyl-carbonyloxy-methyl)-tetrahydropyranyl)oxy-ethyl,2R-(3S,4S,5R-trihydroxy-6R-(hydroxy-methyl)-tetrahydropyranyl)oxy-ethyland3-(2R-(3S,4S,5R,6R-tetrahydroxy-tetrahydropyrantl)-methoxy-carbonyl-amino)-n-propyl.

In another embodiment of the present invention, R² is selected from thegroup consisting of methyl, ethyl, n-propyl, isopropyl, t-butyl,isobutyl, isopentyl, 3-n-heptyl, n-nonyl, amino-methyl, 2-amino-ethyl,2-cyano-ethyl, 4-carboxy-n-butyl, 3-n-heptyl, 4-n-heptyl,3-amino-n-propyl, 3,3,3-trifluoro-n-propyl, 3,3,3-trifluoro-isobutyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,2-phenyl-cyclopropyl, cyclopentyl-methyl, cyclopentyl-ethyl,1-(1-aminocarbonyl-cyclopropyl), 4-hydroxy-cyclohexyl,4-carboxy-cyclohexyl, cis-(4-carboxy)-cyclohexyl,trans-(4-carboxy)-cyclohexyl, 4-methoxy-carbonyl-cyclohexyl,4-ethoxy-carbonyl-cyclohexyl, (1)-(S)-((4R)-methoxy-carbonyl-cyclohexyl,(1)-(R)-((4S)-methoxy-carbonyl-cyclohexyl, 2-methyl-cyclohexyl,4-methyl-cyclohexyl, 4-n-pentyl-cyclohexyl, 4-t-butyl-cyclohexyl,(1)-(S)-2-(R)-methyl-cyclopentyl, 3-methoxy-cyclohexyl,1-(1-(4-chlorophenyl)-cyclopentyl), 4-trifluoromethyl-cyclohexyl,4-oxo-cyclohexyl, phenyl, benzyl, phenyl-ethyl, 3-cyano-phenyl,4-methyl-phenyl, 4-t-butyl-phenyl, 4-n-butyl-phenyl, 2-methoxy-phenyl,3-methoxy-phenyl, 4-dimethylamino-phenyl,4-(methylcarbonylamino)-phenyl, 1-naphthyl-methyl,1-(1,2,3,4-tetrahydro-naphthyl), 4-biphenyl, benzhydryl, 1-adamantyl,2-adamantyl, 2-(R)-adamantyl, 2-(S)-adamantyl, N-piperidinyl,1-(2-methyl-piperidinyl), 1-(4-methyl-piperidinyl),1-(4-isoproyl-piperidinyl), 4-(1-methylcarbonyl)-piperidinyl),3-(2,5-dimethyl-furyl), 4-tetrahydropyranyl,4-(2-phenyl-thiazolyl)-methyl, 4-(1-phenyl-pyrazolyl)-methyl,5-(3-methyl-isoxazolyl)-methyl, 3-(5-phenyl-isoxazolyl)-methyl,1-(2-(N-methyl-N-cyclohexylaminocarbonyl)-pyrrolidinyl),1,4-dioxaspiro[4.5]dec-8-yl, 2-(bicyclo[2.2.1]heptyl),1-(3-n-pentyl-bicyclo[2.2.2]-octyl, 2-bicyclo[2.2.2]octyl,2-(R)-bicyclo[2.2.2]octyl and 2-(S)-bicyclo[2.2.2]octyl.

In an embodiment of the present invention, R² is selected from the groupconsisting of isopropyl, n-butyl, t-butyl, 1-ethyl-n-pentyl, isopentyl,3-n-heptyl, 4-n-heptyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopentyl-methyl-, 2-methyl-cyclohexyl,3-methoxy-cyclohexyl, phenyl, phenylethyl-, 4-(1-methyl-piperidinyl),1-(1-(4-chlorophenyl)-cyclopentyl), 1-adamantyl and 2-adamantyl.

In another embodiment of the present invention, R² is selected from thegroup consisting of isopropyl, t-butyl, 1-ethyl-n-pentyl, isopentyl,3-n-heptyl, 4-n-heptyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentyl-methyl-, 2-methyl-cyclohexyl, phenyl,4-(1-methyl-piperidinyl), 1-(1-(4-chlorophenyl)-cyclopentyl),1-adamantyl and 2-adamantyl.

In another embodiment of the present invention, R² is selected from thegroup consisting of isopentyl, 4-n-heptyl, cyclopentyl, cyclohexyl,cyclopentyl-methyl-, 1-(1-(4-chlorophenyl)-cyclopentyl), 1-adamantyl and2-adamantyl.

In another embodiment of the present invention, R² is selected from thegroup consisting of carboxy-methyl, 2-cyanoethyl-, n-propyl, isopropyl,n-butyl, isobutyl, t-butyl, isopentyl, 3-n-heptyl, 4-n-heptyl,4-carboxy-n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopentyl-methyl-, cyclopentyl-ethyl-,1-(S)-(1-carboxy-2-hydroxy-ethyl), 1-(R)-(1-carboxy-2-hydroxy-ethyl),1-(R)-(1-carboxy-2-t-butoxy-ethyl),1-(S)-(1-methoxy-carbonyl-2-benzyloxy-ethyl),1-(R)-(1-methoxy-carbonyl-2-benzyloxy-ethyl),1-(S)-(1-carboxy-2-benzyloxy-ethyl), 1-(R)-(-carboxy-2-benzyloxy-ethyl),trans-2-methyl-cyclohexyl-, 1-(1-(4-chlorophenyl)-cyclopentyl),3-methoxy-cyclohexyl, 4-hydroxy-cyclohexyl,1-cis-(3-carboxy-cyclohexyl), 4-carboxy-cyclohexyl,(1)-(S)-((4R)-carboxy-cyclohexyl), (1)-(R)-((4S)-carboxy-cyclohexyl),4-(ethoxy-carbonyl)-cyclohexyl, cis-(4-methoxy-carbonyl)-cyclohexyl,trans-(4-methoxy-carbonyl)-cyclohexyl, 1-4-oxo-cyclohexyl,1-cis-(4-amino-carbonyl-cyclohexyl), phenyl, 2-methoxyphenyl,2-methylphenyl, benzyl, phenylethyl-, benzhydryl,4-(1-isopropyl)-piperidinyl, 4-(1-methyl-piperidinyl), 1-adamantyl,2-adamantyl, 4-(tetrahydropyranyl), 5-(3-methyl-isoxazolyl)-methyl,1,4-oxaspiro[4.5]dec-8-yl and 5-tetrazolyl-methyl.

In an embodiment of the present invention, R² is selected from the groupconsisting of 2-cyanoethyl-, n-propyl, isopropyl, n-butyl, isobutyl,t-butyl, isopentyl, 3-n-heptyl, 4-n-heptyl, 4-carboxy-n-butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentyl-methyl-, cyclopentyl-ethyl-, trans-2-methyl-cyclohexyl-,1-(1-(4-chlorophenyl)-cyclopentyl), 3-methoxy-cyclohexyl,4-hydroxy-cyclohexyl, 4-carboxy-cyclohexyl,(1)-(S)-((4R)-carboxy-cyclohexyl), (1)-(R)-((4S)-carboxy-cyclohexyl),4-(ethoxy-carbonyl)-cyclohexyl, cis-(4-methoxy-carbonyl)-cyclohexyl,trans-(4-methoxy-carbonyl)-cyclohexyl, 1-4-oxo-cyclohexyl, phenyl,2-methoxyphenyl, 2-methylphenyl, benzyl, phenylethyl-, benzhydryl,4-(1-isopropyl)-piperidinyl, 4-(1-methyl-piperidinyl), 1-adamantyl,2-adamantyl, 4-(tetrahydropyranyl), 5-(3-methyl-isoxazolyl)-methyl and1,4-oxaspiro[4.5]dec-8-yl.

In another embodiment of the present invention, R² is selected from thegroup consisting of carboxy-methyl, isopropyl, isobutyl, t-butyl,isopentyl, 3-n-heptyl, 4-n-heptyl, 4-carboxy-n-butyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclopentyl-methyl-,cyclopentyl-ethyl-, 1-(S)-(1-carboxy-2-hydroxy-ethyl),1-(R)-(1-carboxy-2-hydroxy-ethyl), 1-(R)-(1-carboxy-2-t-butoxy-ethyl),1-(S)-(1-methoxy-carbonyl-2-benzyloxy-ethyl),1-(R)-(1-methoxy-carbonyl-2-benzyloxy-ethyl),1-(S)-(1-carboxy-2-benzyloxy-ethyl), trans-2-methyl-cyclohexyl-,1-(1-(4-chlorophenyl)-cyclopentyl), 3-methoxy-cyclohexyl,4-hydroxy-cyclohexyl, 1-cis-(3-carboxy-cyclohexyl),4-carboxy-cyclohexyl, (1)-(S)-((4R)-carboxy-cyclohexyl),(1)-(R)-((4S)-carboxy-cyclohexyl), cis-(4-methoxy-carbonyl)-cyclohexyl,trans-(4-methoxy-carbonyl)-cyclohexyl,1-cis-(4-amino-carbonyl-cyclohexyl), phenyl, 2-methylphenyl,phenylethyl-, 4-(1-methyl-piperidinyl), 1-adamantyl, 2-adamantyl,4-(tetrahydropyranyl), 5-(3-methyl-isoxazolyl)-methyl and5-tetrazolyl-methyl.

In another embodiment of the present invention, R² is selected from thegroup consisting of isopropyl, isobutyl, t-butyl, isopentyl, 3-n-heptyl,4-n-heptyl, 4-carboxy-n-butyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopentyl-methyl-, cyclopentyl-ethyl-,trans-2-methyl-cyclohexyl-, 1-(1-(4-chlorophenyl)-cyclopentyl),3-methoxy-cyclohexyl, 4-hydroxy-cyclohexyl, 4-carboxy-cyclohexyl,(1)-(S)-((4R)-carboxy-cyclohexyl), (1)-(R)-((4S)-carboxy-cyclohexyl),cis-(4-methoxy-carbonyl)-cyclohexyl,trans-(4-methoxy-carbonyl)-cyclohexyl, phenyl, 2-methylphenyl,phenylethyl-, 4-(1-methyl-piperidinyl), 1-adamantyl, 2-adamantyl,4-(tetrahydropyranyl) and 5-(3-methyl-isoxazolyl)-methyl.

In another embodiment of the present invention, R² is selected from thegroup consisting of carboxy-methyl, isobutyl, isopentyl,1-(1-(R)-carboxy-2-hydroxy-ethyl), 1-(1-(R)-carboxy-2-t-butoxy-ethyl),1-(1-(S)-carboxy-2-benzyloxy-ethyl), cyclopentyl, cyclohexyl,4-carboxy-cyclohexyl, (1)-(S)-((4R)-carboxy-cyclohexyl), 1-adamantyl and2-adamantyl.

In another embodiment of the present invention, R² is selected from thegroup consisting of isobutyl, isopentyl, cyclopentyl, cyclohexyl,4-carboxy-cyclohexyl, (1)-(S)-((4R)-carboxy-cyclohexyl), 1-adamantyl and2-adamantyl.

In an embodiment of the present invention, L¹ is selected from the groupconsisting of —O—, —S(O)₀₋₂—, —C(O)—, —C(S)—, —C₁₋₄alkyl- and (hydroxysubstituted C₁₋₄alkyl)-. In another embodiment of the present invention,L¹ is selected from the group consisting of —O—, —C(O)—, —CH₂— and—C(OH)—. In another embodiment of the present invention, L¹ is selectedfrom the group consisting of —O—, —C(O)—, —CH₂— and —C(OH)—.

In an embodiment of the present invention, L¹ is selected from the groupconsisting of —C(O)— and —O—. In another embodiment of the presentinvention, L¹ is —O—.

In an embodiment of the present invention, L¹ is selected from the groupconsisting of —C(O)— and —(O)—. In another embodiment of the presentinvention, L¹ is —(O)—;

In an embodiment of the present invention, R³ is selected from the groupconsisting of C₁₋₆alkyl, C₂₋₆alkenyl, cycloalkyl, partially unsaturatedcarbocyclyl, aryl, C₁₋₄aralkyl, biphenyl, heteroaryl andheterocycloalkyl; wherein the cycloalkyl, partially unsaturatedcarbocyclyl, aryl, heteroaryl or heterocycloalkyl, whether alone or aspart of a substituent group is optionally substituted with one to twosubstituents independently selected from halogen, hydroxy, oxo, carboxy,C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, halogen substituted C₁₋₄alkyl,cyano substituted C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,halogen substituted C₁₋₄alkoxy, nitro, cyano, —R⁵, —O—R⁵, —S—R⁵, —NH₂,—N(R^(P))—R⁵, —C(O)—R⁵, —C(O)—NH₂, —C(O)—NR^(P)—R⁵, —NR^(P)—C(O)—R⁵,—NR^(P)—C(O)O—R⁵ and —SO₂—NR^(P)—R⁵.

In another embodiment of the present invention, R³ is selected from thegroup consisting of C₂₋₆alkenyl, aryl, biphenyl, partially unsaturatedcarbocyclyl and heteroaryl; wherein the aryl or heteroaryl group isoptionally substituted with one to two substituents independentlyselected from hydroxy, halogen, C₁₋₄alkyl, C₁₋₄alkoxy, —S—C₁₋₄alkyl,hydroxy substituted C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, —C(O)—NH₂,—C(O)—C₁₋₄alkyl, —NH—C₁₋₄alkyl-cycloalkyl, —NH—C(O)—C₁₋₄alkyl,—NH—C(O)—O—C₁₋₄aralkyl, —SO₂—NH—C₁₋₄alkyl or —SO₂—NH-phenyl.

In another embodiment of the present invention, R³ is selected from thegroup consisting of n-penten-1-yl, phenyl, 2-hydroxy-phenyl,2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2-fluoro-phenyl,4-fluorophenyl, 2,6-difluoro-phenyl, 2-methyl-phenyl, 3-methyl-phenyl,4-methyl-phenyl, 2-methoxy-phenyl, 4-methoxy-phenyl,3,5-dimethoxy-phenyl, 2,6-dimethoxy-phenyl, 2-isopropyl-phenyl,2-methylthio-phenyl, 2-fluoro-6-methoxy-phenyl,2-methoxy-5methyl-phenyl, 2-methoxy-5-fluoro-phenyl,3-(hydroxymethyl)-phenyl, 3-trifluoromethyl-phenyl,2-(methylcarbonylamino)-phenyl, 2-(t-butylaminosulfonyl)-phenyl,2-(aminocarbonyl)-phenyl, 2-(methylsulfonylamino)-phenyl,3-(methylcarbonyl)-phenyl, 3-(benzyloxycarbonylamino)-phenyl,3-(N-(cyclohexylmethyl)-amino)-phenyl, 3-(phenylsulfonylamino)-phenyl,2-naphthyl, 1-cyclohexenyl, 1-cyclopentenyl, 2-biphenyl, 5-pyrimidinyl,4-pyridyl, 3-quinolinyl and 3-(6-fluoro-benzo[d]isoxazolyl).

In an embodiment of the present invention, R³ is selected from the groupconsisting of phenyl, 2-methoxyphenyl,3-(benzyloxy-carbonyl-amino)-phenyl,3-(N-(cyclohexyl-methyl)-amino)-phenyl and3-(phenyl-sulfonyl-amino)-phenyl. In another embodiment of the presentinvention, R³ is selected from the group consisting of phenyl,2-methoxyphenyl, 3-(benzyloxy-carbonyl-amino)-phenyl and3-(phenyl-sulfonyl-amino)-phenyl. In yet another embodiment of thepresent invention, R³ is selected from the group consisting of phenyland 2-methoxyphenyl.

In an embodiment of the present invention, R³ is selected from the groupconsisting of phenyl, 2-hydroxyphenyl, 2-fluorophenyl,2,6-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 2-methylphenyl,3-methylphenyl, 2-methoxy-phenyl, 2-fluoro-6-methoxyphenyl,3-hydroxymethyl-phenyl and 3-(phenyl-sulfonyl-amino)-phenyl. In anotherembodiment of the present invention, R³ is selected from the groupconsisting of phenyl, 2-fluorophenyl, 2,6-difluorophenyl,2-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 2-methoxy-phenyl and2-fluoro-6-methoxyphenyl. In another embodiment of the presentinvention, R³ is selected from the group consisting of phenyl,2-fluorophenyl and 2-methoxy-phenyl.

In an embodiment of the present invention, R⁵ is selected from the groupconsisting of C₁₋₄alkyl, aryl, C₁₋₄aralkyl, cycloalkyl andcycloalkyl-C₁₋₄alkyl-; wherein the aryl, whether alone or as part of asubstituent group is optionally substituted with one to two substituentindependently selected from C₁₋₄alkyl, C₁₋₄alkoxy, halogen, hydroxy,carboxy, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, cyano or nitro.

In an embodiment of the present invention, R^(P) is selected from thegroup consisting of hydrogen, C₁₋₈alkyl, hydroxy substituted C₁₋₄alkyl,C₁₋₄aralkyloxy substituted C₁₋₄alkyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl and C₁₋₄aralkyl; wherein the cycloalkyl, aryl,heteroaryl,.heterocycloalkyl or spiro-heterocyclyl, whether alone or aspart of a substituent group is optionally substituted with one to twosubstituents independently selected from halogen, hydroxy, oxo, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy-carbonyl, nitro, cyano, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, —SO₂—N(R^(S)R^(T)), 5-tetrazolyl or1-(1,4-dihydro-tetrazol-5-one); and wherein each R^(S) and R^(T) isindependently selected from hydrogen or C₁₋₄alkyl.

In an embodiment of the present invention, R¹⁰ is selected from thegroup consisting of hydroxy, halogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogensubstituted C₁₋₄alkyl, halogen substituted C₁₋₄alkoxy; provided that thehalogens on the halogen substituted C₁₋₄alkyl and the halogensubstituted C₁₋₄alkoxy are selected from fluoro or chloro. In anotherembodiment of the present invention, R¹⁰ is selected from the groupconsisting of halogen. In another embodiment of the present invention,R¹⁰ is fluoro.

In an embodiment of the present invention, R¹ is selected from the groupconsisting of hydrogen, methyl and methylcarbonyl. In another embodimentof the present invention, R¹ is hydrogen. In another embodiment of thepresent invention, R¹ is selected from the group consisting of hydrogenand methoxy.

In an embodiment of the present invention, c is an integer from 0 to 1.In another embodiment of the present invention, c is 1.

In an embodiment of the present invention, A² is selected from the groupconsisting of C₁₋₄alkyl; wherein the C₁₋₄alkyl is optionally substitutedwith an R^(Y) substituent; wherein R^(Y) is selected from the groupconsisting of C₁₋₄alkyl, aryl, C₁₋₄aralkyl and cycloalkyl-C₁₋₄alkyl-. Inanother embodiment of the present invention, A² is selected from thegroup consisting of —CH₂—, —CH(CH₂CH₃)—, —CH(phenyl)-, —CH(benzyl)- and—CH(cyclohexylmethyl)-.

In another embodiment of the present invention, A² is selected from thegroup consisting of —CH₂— and —CH(CH₂CH₃)—. In another embodiment of thepresent invention, A² is —CH₂—.

In another embodiment of the present invention, A² is selected from thegroup consisting of —CH₂—, —CH(CH₂CH₃)—, —CH(phenyl)- and—CH(cyclohexyl)-. In yet another embodiment of the present invention, A²is selected from the group consisting of —CH₂—, —CH(CH₂CH₃)— and—CH(cyclohexyl)-. In another embodiment of the present invention, A² is—CH₂—.

In an embodiment of the present invention,

is selected from the group consisting of aryl, aryl-C₁₋₄alkyl-,cycloalkyl, heteroaryl and heterocycloalkyl; wherein the aryl,cycloalkyl, heteroaryl or heterocycloalkyl group, whether alone or aspart of a substituet group, is optionally substituted with one to twosubstituents independently selected from C₁₋₄alkyl, C₁₋₄alkoxy, halogensubstituted C₁₋₄alkyl, halogen substituted C₁₋₄alkoxy, hydroxysubstituted C₁₋₄alkyl, hydroxy, carboxy, cyano, nitro, amino,C₁₋₄alkylamino or di(C₁₋₄alkyl)amino; provided that when c is 0, then

is other than aryl or heteroaryl.

In an embodiment of the present invention,

is selected from the group consisting of cycloalkyl, aryl,aryl-C₁₋₄alkyl-, heteroaryl, and heterocycloalkyl; wherein the aryl,heteroaryl or heterocycloalkyl, whether alone or as part of asubstituent group, is optionally substituted with one to twosubstituents independently selected from C₁₋₄alkyl or C₁₋₄alkoxy;provided that when c is 0, then

is other than aryl or heteroaryl.

In another embodiment of the present invention,

is selected from the group consisting of cyclopentyl, (S)-cyclopentyl,(R)-cyclopentyl, cyclohexyl, (R)-cyclohexyl, (S)-cyclohexyl,trans-cyclohexyl, phenyl, benzyl, 9-fluorenyl, 3-pyrrolidinyl,1-indanyl, 1-(5-methoxy-indanyl)-methyl, 3-piperidinyl, 4-piperidinyl,3-azepinyl, 2-pyridyl, 4-pyridyl, 2-furyl, 2-thienyl and 5-oxazolyl;provided that when-c is 0, then

is other than phenyl.

In an embodiment of the present invention,

is selected from the group consisting of phenyl, 4-piperidinyl and4-pyridyl; provided that when c is 0, then

is other than phenyl. In another embodiment of the present invention,

is selected from the group consisting of phenyl and 4-piperidinyl;provided that when c is 0, then

is 4-piperidinyl. In yet another embodiment of the present invention, cis 1 and

is phenyl.

In an embodiment of the present invention,

is selected from the group consisting of phenyl, 2-pyridyl and 2-furyl.In another embodiment of the present invention,

is selected from the group consisting of phenyl and 2-pyridyl.

In an embodiment of the present invention, Q³ is selected from the groupconsisting of —C(O)—, —C(O)O—, —C(O)—NH—, —C(O)—N(C₁₋₈alkyl)-,—C(O)—N(cycloalkyl)-, —NH—C(O)— and —NH—C(O)O—; wherein the cycloalkylis optionally substituted with C₁₋₄alkyl.

In another embodiment of the present invention, Q³ is selected from thegroup consisting of —C(O)—, —C(O)—NH—, —C(O)—N(CH₃)—, —(R)—C(O)—N(CH₃),—(S)—C(O)—N(CH₃), —C(O)—N(isopropyl)-, —C(O)—N(n-propyl)-,—C(O)—N(isobutyl)-, —C(O)—N(2-ethyl-n-hexyl)-, —C(O)—N(cyclohexyl)-,—C(O)—N(4-methyl-cyclohexyl)-, —C(O)O—, —NH—C(O)— and —NH—C(O)O—.

In an embodiment of the present invention, Q³ is selected from the groupconsisting of -1-C(O)O—, -3-C(O)O—, -2-C(O)—N(CH₃)— and -3-C(O)—N(CH₃)—.In another embodiment of the present invention, Q³ is selected from thegroup consisting of -1-C(O)O—, -3-C(O)O— and -3-C(O)—N(CH₃)—. In anotherembodiment of the present invention, Q³ is -3-C(O)—N(CH₃)—.

In an embodiment of the present invention, Q³ is selected from the groupconsisting of -3-C(O)—N(CH₃)—, -3-C(O)—N(isopropyl)-,-3-C(O)—N(isobutyl)-, -3-C(O)—N(cyclohexyl)-, -4-C(O)—N(CH₃)— and5-C(O)—N(CH₃)—. In another embodiment of the present invention, Q³ isselected from the group consisting of -3-C(O)—N(CH₃)—,-3-C(O)—N(isopropyl)-, -3-C(O)—N(cyclohexyl)- and -4-C(O)—N(CH₃)—. Inanother embodiment of the present invention, Q³ is -3-C(O)—N(CH₃)—.

In an embodiment of the present invention, R² is selected from the groupconsisting of C₁₋₈alkyl, cycloalkyl, cycloalkyl-C₁₋₄alkyl-, aryl,C₁₋₄aralkyl, heteroaryl, heteroaryl-C₁₋₄alkyl-, heterocycloalkyl andheterocycloalkyl-C₁₋₄alkyl-; wherein the C₁₋₈alkyl, cycloalkyl, aryl orheterocycloalkyl, whether alone or as part of a substituent group isoptionally substituted with one to three halogen, C₁₋₄alkyl, —SO₂—NH₂ orphenyl.

In another embodiment of the present invention, R² is selected from thegroup consisting of trifluoromethyl, methyl, ethyl, isobutyl, t-butyl,3-n-heptyl, 4-n-heptyl, 2-ethyl-n-hexyl, cyclopentyl, cyclohexyl,4-methyl-cyclohexyl, cyclopropyl-methyl, 4-aminosulfonyl-phenylethyl,benzhydryl, 1-adamantyl, 2-adamantyl, 2-(R)-adamantyl, 2-(S)-adamantyl,2-decahydro-isoquinolinyl, 2-(1-methyl-pyrrolidinyl)-ethyl,1-piperidinyl and 4-(1-methyl-piperidinyl).

In another embodiment of the present invention, R² is selected from thegroup consisting of methyl, ethyl, t-butyl and cyclohexyl. In anembodiment of the present invention, R² is selected from the groupconsisting of isobutyl and cyclohexyl. In another embodiment of thepresent invention, R² is cyclohexyl.

In an embodiment of the present invention, L¹ is selected from the groupconsisting of —O—, —S—, —NH—, —C₁₋₄alkyl- and —C₂₋₄alkenyl-. In anotherembodiment of the present invention, L¹ is selected from the groupconsisting of —O—, —S—, —NH—, —CH(CH₃)— and —CH═CH—. In anotherembodiment of the present invention, L¹ is selected from the groupconsisting of —O—, —S— and —NH—. In another embodiment of the presentinvention, L¹ is selected from the group consisting of —O— and —S—.

In an embodiment of the present invention, R³ is selected from the groupconsisting of C₁₋₄alkyl, cycloalkyl, cycloalkyl-C₁₋₄alkyl-, aryl,heteroaryl and heterocycloalkyl; wherein the cycloalkyl or aryl, whetheralone or as art of a substituent group is optionally substituted withone to two substituents independently selected from halogen, hydroxy,carboxy, cyano, nitro, amino, C₁₋₄alkylamino, di(C₁₋₄alkylamino),C₁₋₄alkyl, C₂₋₄alkenyl, C₁₋₄alkoxy, hydroxy substituted C₁₋₄alkyl,halogen substituted C₁₋₄alkyl, cyano substituted C₁₋₄alkyl, halogensubstituted C₁₋₄alkoxy, —O-aryl, —O—C₁₋₄aralkyl, —S—C₁₋₄alkyl,—SO₂—C₁₋₄alkyl, —C(O)—C₁₋₄alkyl, —C(O)—NH₂, —C(O)—NH(C₁₋₄alkyl),—C(O)—N(C₁₋₄alkyl)₂, —NH—C(O)—C₁₋₄alkyl, —C(O)—NH—C₁₋₄alkyl,—NH—SO₂—C₁₋₄alkyl, —NH—SO₂-phenyl, aryl, C₁₋₄aralkyl, cycloalkyl,cycloalkyl-C₁₋₄alkyl-, heteroaryl, heteroaryl-C₁₋₄alkyl-heterocycloalkylor heterocycloalkyl-C₁₋₄alkyl-; and wherein the aryl, cycloalkyl,heteroaryl or heterocycloalkyl substituent, whether alone or as part ofa substituent group, is optionally substituted with one to threesubstituents independently selected from C₁₋₄alkyl or C₁₋₄alkoxy.

In another embodiment of the present invention, R³ is selected from thegroup consisting of n-pentyl, isopentyl, isobutyl, isopropyl,cyclopentyl, cyclopentyl-methyl, phenyl, 2-hydroxy-phenyl,3-carboxy-phenyl, 2-cyano-phenyl, 2-nitro-phenyl, 2-bromo-phenyl,2-fluoro-phenyl, 2-chloro-phenyl, 2,6-dichloro-phenyl, 2-methyl-phenyl,3-methyl-phenyl, 2-ethyl-phenyl, 4-isopropyl-phenyl,3,4-dimethyl-phenyl, 3,5-dimethyl-phenyl, 2,6-dimethyl-phenyl,2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl,3,4-dimethoxy-phenyl, 2,6-dimethoxy-phenyl, 2-ethoxy-phenyl,3-ethoxy-phenyl, 2-isopropoxy-phenyl, 2-methoxy-5-methyl-phenyl,2-methoxy-6-methyl-phenyl, 2-trifluoromethyl-phenyl,2-trifluoromethoxy-phenyl, 2-methylthio-phenyl, 4-methylthio-phenyl,2-hydroxymethyl-phenyl, 2-cyanomethyl-phenyl, 2-(aminocarbonyl)-phenyl,4-(aminocarbonyl)-phenyl, 2-(dimethylaminocarbonyl)-phenyl,3-(dimethylamino)-phenyl, 4-(dimethylamino)-phenyl,2-allyl-6-methyl-phenyl, 2-allyl-6-ethoxy-phenyl,2-methyl-6-n-propyl-phenyl, 3-(methylcarbonylamino)-phenyl,2-(methylaminocarbonyl)-phenyl, 2-(methylcarbonyl)-phenyl,4-(methylcarbonylamino)-phenyl, 2-(aminocarbonylmethyl)-phenyl,2-(methylsulfonyl)-phenyl,(3-(2-methoxy-4-methyl-phenyl)-sulfonylamino)-phenyl,3-(2,4,6-trimethylphenylsulfonylamino)-phenyl,3-(phenylsulfonylamino)-phenyl, 2-(t-butylaminosulfonyl)-phenyl,2-(t-butylcarbonylamino)-5-methoxy-phenyl,3-(phenylsulfonylamino)-phenyl, 2-phenoxy-phenyl, 3-phenoxy-phenyl,2-benzyloxy-phenyl, 2-(2-benzthiazolyl)-5-methoxy-phenyl,2-(2-benzthiazolyl)-phenyl, 2-(1-pyrrolyl)-phenyl,3-(2-quinolinyl)-phenyl, 2-(1-pyrrolidinyl-methyl)-phenyl,2-cyclopentyl-phenyl, 4-cyclohexyl-phenyl, 4-(4-morpholinyl)-phenyl,3-methoxy-benzyl, 1-naphthyl, 2-naphthyl,2-(5,6,7,8-tetrahydro-naphthyl), 2-biphenyl, 3-biphenyl,2-biphenyl-methyl, 3-pyridyl, 3,4-methylenedioxyphenyl,4(3,5-dimethyl-isoxazolyl), 4-pyrazolyl, 3-thienyl, 3-pyridyl,4-pyridyl, 5-indolyl and 3-benzothienyl.

In an embodiment of the present invention, R³ is selected from the groupconsisting of phenyl, 2-bromophenyl, 2-chlorophenyl, 2,6-dichlorophenyl,2-hydroxy-phenyl, 2-hydroxymethyl-phenyl, 2-methoxy-phenyl,3-methoxy-phenyl, 2-ethoxy-phenyl, 2-methylthio-phenyl,2-cyanomethyl-phenyl, 3-(phenyl-sulfonyl-amino)-phenyl,3-(2,4,6-trimethylphenyl-sulfonyl-amino)-phenyl,(3-(2-methoxy-4-methyl-phenyl)-sulfonyl-amino)-phenyl,2-(t-butyl-carbonyl-amino)-5-methoxy-phenyl, 1-naphthyl, 3-thienyl and4-(3,5-dimethylisoxazolyl).

In another embodiment of the present invention, R³ is selected from thegroup consisting of phenyl, 2-bromophenyl, 2-chlorophenyl,2,6-dichlorophenyl, 2-hydroxy-phenyl, 2-hydroxymethyl-phenyl,2-methoxy-phenyl, 3-methoxy-phenyl, 2-ethoxy-phenyl,2-methylthio-phenyl, 2-cyanomethyl-phenyl,3-(phenyl-sulfonyl-amino)-phenyl, 1-naphthyl and 3-thienyl. In anotherembodiment of the present invention, R³ is selected from the groupconsisting of phenyl, 2-methoxy-phenyl, 2-ethoxy-phenyl and 1-naphthyl.

In an embodiment of the present invention, R³ is selected from the groupconsisting of phenyl, 2-bromophenyl, 2-fluorophenyl, 2-chlorophenyl,2,6-dichlorophenyl, 2-hydroxyphenyl, 2-hydroxymethyl-phenyl,2-methylphenyl, 3-methylphenyl, 2,6-dimethylphenyl, 2-methoxyphenyl,3-methoxyphenyl, 2,6-dimethoxyphenyl, 2-ethoxyphenyl,2-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 2-methylthio-phenyl,2-nitrophenyl, 2-cyanophenyl, 2-cyanomethyl-phenyl, 2-phenoxy-phenyl,2-(methyl-carbonyl-amino)-phenyl, 2-(amino-carbonyl)-phenyl,3-(phenyl-sulfonyl-amino)-phenyl, 2-(t-butyl-amino-sulfonyl)-phenyl,2-(t-butyl-carbonyl-amino)-5-methoxy-phenyl, 4-(3,5-dimethyl-soxazolyl),1-naphthyl, 3-thienyl and 3-pyridyl.

In another embodiment of the present invention, R³ is selected from thegroup consisting of phenyl, 2-bromophenyl, 2-fluorophenyl,2-chlorophenyl, 2-hydroxyphenyl, 2-hydroxymethyl-phenyl, 3-methylphenyl,2-methoxyphenyl, 2-ethoxyphenyl, 2-cyanomethyl-phenyl,2-(t-butyl-carbonyl-amino)-5-methoxy-phenyl, 1-naphthyl and 3-thienyl.

In another embodiment of the present invention, R³ is selected from thegroup consisting of 2-methoxyphenyl and 2-ethoxyphenyl.

In an embodiment of the present invention, R⁶ is selected from the groupconsisting of C₁₋₆alkyl and hydroxy substituted C₁₋₆alkyl. In anotherembodiment of the present invention, R⁶ is selected from the groupconsisting of n-propyl, 4-hydroxy-n-butyl and 5-hydroxy-n-pentyl.

In an embodiment of the present invention, R⁶ is selected from the groupconsisting of n-propyl, 4-hydroxy-n-butyl and 5-hydroxy-n-pentyl. Inanother embodiment of the present invention, R⁶ is selected from thegroup consisting of n-propyl and 4-hydroxy-n-butyl. In anotherembodiment of the present invention, R⁶ is n-propyl.

In an embodiment of the present invention d is an integer from 0 to 1.In another embodiment of the present invention, d is 1.

In an embodiment of the present invention, L² is selected from the groupconsisting of —O—, —S(O)₀₋₂— and —NH—. In another embodiment of thepresent invention, L² is selected from the group consisting of —O—, —S—,—SO— and —SO—. In yet another embodiment of the present invention, L² isselected from the group consisting of —O—, —S— and —SO—. In anotherembodiment of the present invention, L² is selected from the groupconsisting of—O— and —S—. In yet another embodiment of the presentinvention, L² is —O—.

In an embodiment of the present invention, R⁷ is selected from the groupconsisting of cycloalkyl, cycloalkyl-C₁₋₄alkyl, aryl, C₁₋₄alkyl-aryl,aryl-C₁₋₄alkyl, heteroaryl, heteroaryl-C₁₋₄alkyl, heterocycloalkyl andheterocycloalkyl-C₁₋₄alkyl; wherein the aryl, cycloalkyl, partiallyunsaturated carbocyclyl, heteroaryl or heterocycloalkyl group isoptionally substituted with one to two substituents independentlyselected from C₁₋₄alkyl, C₁₋₄alkoxy, halogen substituted C₁₋₄alkyl,halogen substituted C₁₋₄alkoxy, hydroxy substituted C₁₋₄alkyl, hydroxy,carboxy, cyano, nitro, amino, C₁₋₄alkylamino or di(C₁₋₄alkyl)amino.

In another embodiment of the present invention, R⁷ is selected from thegroup consisting of aryl, C₁₋₄alkyl-aryl and aryl-C₁₋₄alkyl. In anotherembodiment of the present invention, R⁷ is selected from the groupconsisting of phenyl, —CH₂-phenyl-, -phenyl-3-CH₂— and-phenyl-2-CH₂—CH₂—.

In an embodiment of the present invention, R⁷ is selected from the groupconsisting of -phenyl-, -phenyl-3-CH₂— and phenyl-2-CH₂—CH₂—. In anotherembodiment of the present invention, R⁷ is selected from the groupconsisting of -phenyl- and -phenyl-3-CH₂—. In another embodiment of thepresent invention, R⁷ is phenyl.

In an embodiment of the present invention, L³ is selected from the groupconsisting of —C(O)—, —C(O)O—, —OC(O)—, —NR^(A)—, —N(CN)—,—NR^(A)—C(O)—, —C(O)—NR^(A)—, —NR^(A)—SO₂—, —SO₂—NR^(A)—, —NR^(A)—C(O)O—and —OC(O)—NR^(A).

In another embodiment of the present invention, L³ is selected from thegroup consisting of —NH—, —N(CN)—, —N(C₁₋₄alkyl)-, —NH—C(O)—, —C(O)—NH—,—NH—SO₂—, —N(C₁₋₄alkyl)-C(O)O— and —N(cycloalkyl)-C(O)O—. In yet anotherembodiment of the present invention, L³ is selected from the groupconsisting of —NH—, —N(CN)—, —N(CH₃)—, —NH—C(O)—, —C(O)—NH—, —NH—SO₂—and —N(cyclohexyl)-C(O)O—; wherein the L³ group is bound at the3-position of the R⁷ group.

In an embodiment of the present invention, L³ is selected from the groupconsisting of —NH—, —N(CN)—, —NH—C(O)—, —NH—C(O)O—,—N(cyclohexyl)-C(O)O— and —NH—SO₂—; wherein the L³ is bound to the R⁷phenyl at the 3-position. In another embodiment of the presentinvention, L³ is selected from the group consisting of —NH—, —NH—C(O)—and —NH—SO₂—; wherein the L³ is bound to the R⁷ phenyl at the3-position. In another embodiment of the present invention, L³ is—NH—SO₂—; wherein the L³ is bound to the R⁷ phenyl at the 3-position.

In an embodiment of the present invention, L³ is selected from the groupconsisting of —NH—C(O)O—, —N(cyclohexyl)-C(O)O—, —NH—, —N(CN)— and—NH—SO₂; wherein the L³ is bound to R⁷ phenyl at the 3-position.

In an embodiment of the present invention, R^(A) is selected from thegroup consisting of hydrogen, C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl,C₁₋₄aralkyloxy substituted C₁₋₄alkyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl,heteroaryl-C₁₋₄alkyl- and heterocycloalkyl-C₁₋₄alkyl-; wherein thecycloalkyl, aryl, heteroaryl or heterocycloalkyl, whether alone or aspart of a substituent group is optionally substituted with one to twosubstituents independently selected from halogen, hydroxy, oxo, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy-carbonyl, nitro, cyano, amino,C₁₋₄alkylamino or di(C₁₋₄alkyl)amino.

In an embodiment of the present invention, R⁸ is selected from the groupconsisting of C₁₋₆alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl,cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl, heteroaryl-C₁₋₄alkyl- andheterocycloalkyl-C₁₋₄alkyl-; wherein the C₁₋₆alkyl, cycloalkyl, aryl,heteroaryl or heterocycloalkyl, whether alone or as part of asubstituent group is optionally substituted with one to two substituentsindependently selected from halogen, hydroxy, carboxy, —C(O)—C₁₋₄alkyl,—C(O)—C₁₋₄aralkyl, —C(O)O—C₁₋₄alkyl, —C(O)O—C₁₋₄aralkyl,—C(O)—N(R^(L)R^(M)), —NR^(L)—C(O)—C₁₋₄alkyl, —SO₂—C₁₋₄alkyl, —SO₂-aryl,—SO₂—N(R^(L)R^(M)), C₁₋₄alkyl, fluoro substituted C₁₋₄alkyl, hydroxysubstituted C₁₋₄alkyl, carboxy substituted C₁₋₄alkyl, C₁₋₄alkoxy, fluorosubstituted C₁₋₄alkoxy, nitro, cyano, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, phenyl or heteroaryl; wherein the phenyl orheteroaryl substituent is optionally substituted with one or moresubstituent independently selected from halogen, hydroxy, carboxy,C₁₋₄alkyl, fluoro substituted C₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano,amino, C₁₋₄alkylamino or di(C₁₋₄alkyl)amino; and wherein each R^(L) andR^(M) is independently selected from the group consisting of hydrogen,C₁₋₄alkyl and C₅₋₈cycloalkyl.

In another embodiment of the present invention, R⁸ is selected from thegroup consisting of C₁₋₄alkyl, cycloalkyl, cycloalkyl-C₁₋₄alkyl, aryl,C₁₋₄aralkyl, heteroaryl and heterocycloalkyl; wherein the aryl orheteroaryl, whether alone or as part of a substituent group isoptionally substituted with one to three substituents independentlyselected from halogen, hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, fluorosubstituted C₁₋₄alkyl, fluoro substituted C₁₋₄alkoxy, cyano, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, —C(O)O—C₁₋₄alkyl,—C(O)—N(R^(L)R^(M))—SO₂—C₁₋₄alkyl, —SO₂-aryl, —NH—C(O)—C₁₋₄alkyl, phenylor heteroaryl; wherein the phenyl or heteroaryl substituent isoptionally substituted with a substituent selected from fluorosubstituted C₁₋₄alkyl; and wherein each R^(L) and R^(M) is independentlyselected from hydrogen, C₁₋₄alkyl or C₅₋₆cycloalkyl.

In yet another embodiment of the present invention, R⁸ is selected fromthe group consisting of methyl, isopropyl, n-butyl, cyclohexyl,cyclohexyl-methyl, phenyl, phenyl-ethyl, phenyl-n-propyl,3-(N-methyl-N-cyclohexyl-amino-carbonyl)-n-propyl, 3-bromo-phenyl,3-methoxy-phenyl, 4-methoxy-phenyl, 2-methoxy-4-methyl-phenyl,2,4,6-trimethyl-phenyl, 2,5-dimethoxy-phenyl, 3,4-dimethoxy-phenyl,3-trifluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 3-cyano-phenyl,2-(methyl-sulfonyl)-phenyl, 4-(methyl-carbonyl-amino)-phenyl,5-carboxy-2-methoxy-phenyl, benzyl, 3-hydroxy-benzyl, 4-methyl-benzyl,2-methoxy-benzyl, 4-methoxy-benzyl, 2,6-dimethoxy-benzyl,2,4,6-trimethyl-benzyl, 1-nahthyl, 2-naphthyl, 1-naphthyl-methyl,1-(5-dimethylamino)-naphthyl, 4-biphenyl, 2-thienyl, 3-thienyl,4-(3,5-dimethyl-isoxazolyl), 3-benzothienyl, 4-benzo[2,3,1]thiadiazolyl,2-(5-(2-pyridyl)-thienyl), 2-(5-(3-(2-methyl-thiazolyl)-thienyl)),2-(5-(3-(5-trifluoromethyl)-isoxazolyl)-thienyl),6-(2,3-dihydro-benzo[1,4]dioxanyl), 3-(2-methoxy-carbonyl)-thienyl,2-(5-(5-isoxazolyl)-thienyl)), 2-(5-bromo-thienyl) and2-(4-phenyl-sulfonyl)-thienyl.

In an embodiment of the present invention, R⁸ is selected from the groupconsisting of n-butyl,3-(N-methyl-N-cyclohexyl-amino-carbonyl)-n-propyl, cyclohexyl,cyclohexyl-methyl-, phenyl, 2-trifluoromethylphenyl,3-trifluoromethoxyphenyl, 3-cyanophenyl, 3-methoxyphenyl,4-methoxyphenyl, 2-methoxy-4-methylphenyl, 2,4,6-trimethylphenyl,benzyl, 2-methoxybenzyl, 4-methoxbenzyl, 2,4,6-trimethylbenzyl,phenylethyl-, 2-thienyl, 3-thienyl, 2-(5-bromo-thienyl) and3-benzothienyl. In another embodiment of the present invention, R⁸ isselected from the group consisting of3-(N-methyl-N-cyclohexyl-amino-carbonyl)-n-propyl, phenyl,2-methoxy-4-methylphenyl, 2,4,6-trimethylphenyl, benzyl,2-methoxybenzyl, 4-methoxybenzyl, 2,4,6-trimethylbenzyl and3-benzothienyl. In yet another embodiment of the present invention, R⁸is 2,4,6-trimethylphenyl.

In an embodiment of the present invention, R⁸ is selected from the groupconsisting of 3-(N-methyl-N-cyclohexyl-amino-carbonyl)-n-propyl,cyclohexyl, cyclohexyl-methyl-, phenyl and benzyl.

In an embodiment of the present invention, R¹⁰ is selected from thegroup consisting of hydroxy, halogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogensubstituted C₁₋₄alkyl and halogen substituted C₁₋₄alkoxy; provided thatthe halogens on the halogen substituted C₁₋₄alkyl or the halogensubstituted C₁₋₄alkoxy are selected from the group consisting of chloroand fluoro.

In an embodiment of the present invention are compounds of formula (I)wherein R³ is other than C₁₋₆alkyl. In another embodiment of the presentinvention R³ is other than C₁₋₆alkyl, wherein the C₁₋₆alkyl issubstituted with —C(O)—NR^(P)-cycloalkyl, preparaby, R³ is other thanC₁₋₆alkyl, wherein the C₁₋₆alkyl is substituted with —C(O)—NR^(P)—R⁵. Inanother embodiment of the present invention R³ is unsubstitutedcyloalkyl, partially unsaturated carbocyclyl, aryl, heteroaryl orheterocycloalkyl. In another embodiment of the present invention R³ is asubstituted or unsubstituted aryl or heteroaryl, wherein thesubstituents are as herein defined.

In an embodiment of the present invention are compounds of formula (I)selected from the group consisting of the compounds listed in Tables 1-6below. In another embodiment of the present invention are compounds offormula (II) selected from the group consisting of the compounds listedin Tables 9-13 below. In another embodiment of the present invention arecompounds of formula (III) selected from the group consisting of thecompounds listed in Tables 7-8 below.

In an embodiment of the present invention are compounds of formula (I)whose Ki, as measured according to the procedure described in Example159, is less than or equal to about 1 μM, preferably, less than or equalto about 250 nM, more preferably, less than or equal to about 100 nM,more preferably still, less than or equal to about 50 nM. In anotherembodiment of the present invention are compounds of formula (II) whoseKi, as measured according to the procedure described in Example 159, isless than or equal to about 1 μM, preferably, less than or equal toabout 250 nM, more preferably, less than or equal to about 100 nM, morepreferably still, less than or equal to about 50 nM. In anotherembodiment of the present invention are compounds of formula (III) whoseKi, as measured according to the procedure described in Example 159, isless than or equal to about 1 μM, preferably, less than or equal toabout 250 nM, more preferably, less than or equal to about 100 nM, morepreferably still, less than or equal to about 50 nM.

In an embodiment of the present invention are compounds of formula (I),whose IC₅₀, as measured according to the procedure described in Example158, is less than or equal to about 1 μM, preferably, less than or equalto about 250 nM, more preferably, less than or equal to about 50 nM. Inanother embodiment of the present invention are compounds of formula(II), whose IC₅₀, as measured according to the procedure described inExample 158, is less than or equal to about 1 μM, preferably, less thanor equal to about 250 nM, more preferably, less than or equal to about50 nM. In another embodiment of the present invention are compounds offormula (III), whose IC₅₀, as measured according to the proceduredescribed in Example 158, is less than or equal to about 1 μM,preferably, less than or equal to about 250 nM, more preferably, lessthan or equal to about 50 nM.

Additional embodiments of the present invention, include those whereinthe substituents selected for one or more of the variables definedherein (e.g. R⁰, R¹, R², R³, R⁶, R⁷, R⁸, R¹⁰, L¹, L², L³, a, b, c, d,A¹, A², Q¹, Q³,

etc.) are independently selected to be any individual substituent or anysubset of substituents selected from the complete list as definedherein.

Representative compounds of the present invention are as listed inTables 1 through 13, below. Unless otherwise noted, all compounds wereprepared as mixtures of stereo-isomers. Representative compounds offormula (I) are as listed in Tables 1-6; compounds of formula (III) areas listed in Tables 7 and 8; and compounds of formula (II) are as listedin Tables 9-13 below.

For substituent groups bound through two points within the structures inthe Tables below, for example R⁷, A¹, A², Q¹, Q³, L¹, L², L³, etc., thesubstituent group is identified as it would be incorporated into thestructure heading the table. Thus, for example in Table 1 wherein A¹ is1-(cyclohexyl)-n-propyl-, the 1- and 3-carbon atoms of the n-propyl arebound to the nitrogen and Q¹ groups respectively, and the cyclohexyl isbound to the 1-carbon of the n-propyl. Similarly, when Q¹ is—C(O)—N(CH₃)—, the carbonyl is bound to A¹ and the nitrogen of themethylamino is bound to the R² group. Similarly, in Table 7, wherein R⁷is —CH-phenyl-, the carbon of the CH₂— is bound to the L³ group and thephenyl is bound to the (L²)_(d) group whereas when R⁷ is -phenyl-3-CH₂—,the phenyl is bound to the L³ group and the carbon of the CH₂— is boundto the (L²)_(d) group. Further, unless otherwise noted, any terminalsubstituent group is bound at the 1-position. Thus for example,4-fluorophenyl corresponds to a phenyl group bound at the 1-position andsubstituted with a fluoro group at the 4-position, and couldalternatively be defined as 1-(4-fluorophenyl). Further, for compoundsof formula

(II) listed in Tables 9-13, unless otherwise noted, the

substituent shall be assumed to be bound at the 1-position, unlessotherwise noted, with the Q³ substituent bound as indicated by thenumbering listed in the Q³ substituent column. TABLE 1 Compounds ofFormula (I)

ID No A¹ Q¹ R² R³ 1 —ethyl— —C(O)—N(CH₃)— cyclohexyl phenyl 2 —ethyl——C(O)—N(CH₃)— cyclohexyl 4-fluoro-phenyl 3 —ethyl— —C(O)—N(CH₂CH₃)—cyclohexyl phenyl 4 —ethyl— —C(O)—N(CH₃)— cycloheptyl phenyl 5 —ethyl——C(O)—N(CH₃)— cycloheptyl 4-fluoro-phenyl 6 —ethyl— —C(O)—N(CH₂CH₃)—cyclohexyl 4-fluoro-phenyl 7 —ethyl— —NH—C(O)— cyclohexyl phenyl 8—n-propyl— —O— phenyl phenyl 10 —n-propyl— —C(O)—N(CH₃)— cyclohexylphenyl 12 —ethyl— —C(O)—N(cyclohexyl)— phenyl phenyl 13 —ethyl——C(O)—N(CH₃)— phenyl phenyl 15 —n-propyl— —N(CH₃)— cyclohexyl phenyl 18—ethyl— —O— methyl phenyl 22 —ethyl— —C(O)—N(CH₃)— isopropyl phenyl 23—ethyl— —N(CH₃)—C(O)— cyclohexyl phenyl 24 —ethyl— —C(O)—N(CH₃)—cyclopentyl phenyl 25 —ethyl— —C(O)—N(CH₃)— cyclopentyl 4-fluoro-phenyl27 —n-butyl— —C(O)—N(CH₃)— cyclohexyl phenyl 30 —n-butyl— —NH—C(O)—cyclohexyl phenyl 31 —n-butyl— —C(O)—NH— cyclohexyl phenyl 39 —ethyl——C(O)—N(cyclohexyl)— cyclohexyl phenyl 40 —ethyl— —C(O)—N(CH₃)—phenylethyl— phenyl 41 —ethyl— —C(O)—N(CH₃)— 1-adamantyl phenyl 42—ethyl— —C(O)—N(CH₃)— 1-naphthyl-methyl— phenyl 43 —ethyl— —C(O)—N(CH₃)—benzyl phenyl 45 —ethyl— —C(O)—N(CH₃)— 1-(1,2,3,4-tetrahydro- phenylnaphthyl) 46 —n-butyl— —C(O)—N(cyclohexyl)— cyclohexyl phenyl 47—n-butyl— —C(O)—N(CH₃)— benzyl phenyl 48 —n-butyl— —C(O)—N(CH₃)—1-adamantyl phenyl 50 —n-butyl— —C(O)—N(CH₃)— phenylethyl— phenyl 51—n-butyl— —C(O)—N(CH₃)— 1-naphthyl-methyl— phenyl 54 —n-butyl——C(O)—N(CH₃)— 1-(1,2,3,4-tetrahydro- phenyl naphthyl) 57 —ethyl——SO₂—N(CH₃)— cyclohexyl phenyl

TABLE 2 Compound of formula (I)

ID No A¹ Q¹ R² (L¹)_(b) R³ 35 —ethyl— —C(O)—N(CH₃)— cyclohexyl 7-C(O)—phenyl 753 1-(S)- —C(O)—N(CH₃)— cyclohexyl 5-O— phenyl (cyclohexyl)-n-propyl— 754 1-(S)- —C(O)—N(CH₃)— cyclohexyl 7-O— phenyl (cyclohexyl)-n-propyl—

TABLE 3 Compounds of Formula (I)

ID No A¹ Q¹ R² R³ 19 —n-butyl— —C(O)—N(cyclohexyl)— cyclohexyl phenyl 20—ethyl— —C(O)—N(CH₃)— cyclohexyl phenyl 65 —ethyl— —C(O)O— ethyl phenyl71 —ethyl— —SO₂—N(CH₃)— cyclohexyl 3-(benzyloxy- carbonyl- amino)-phenyl75 —n-butyl— —C(O)—N(cyclohexyl)— cyclohexyl 3-(benzyloxy- carbonyl-amino)-phenyl 79 —ethyl— —N(ethyl)— ethyl phenyl 80 —ethyl— —NH—C(O)O—t-butyl phenyl 84 1-(N-cyclohexyl-N- —C(O)—N(CH₃)— cyclohexyl phenylmethyl-amino- carbonyl-ethyl)-n- propyl— 85 1-cyclohexyl-n-—C(O)—N(CH₃)— cyclohexyl phenyl propyl— 86 1-(n-propyl)-n- —C(O)—N(CH₃)—cyclohexyl phenyl propyl— 88 —methyl— —C(O)— 1-(2-(S)-(N- phenylmethyl-N- cyclohexyl- aminocarbonyl)- pyrrolidinyl) 901-(n-propyl)-n-butyl— —C(O)—N(CH₃)— cyclohexyl phenyl 911-(n-propyl)-n-butyl— —C(O)—NH— cyclohexyl phenyl 96 —n-butyl——C(O)—N(CH₃)— cyclohexyl 3-(N- (cyclohexyl- methyl)-amino)- phenyl 101—n-butyl— —NH—C(O)O— t-butyl phenyl 103 —n-propyl— —NH—C(O)O— t-butylphenyl 105 1-(n-propyl)-n-butyl— —C(O)—N(ethyl)— cyclohexyl phenyl 1061-(n-propyl)-n-butyl— —C(O)—N(CH₃)— 4-(1-methyl- phenyl piperidinyl) 1071-(cyclohexyl- —NH—C(O)— cyclohexyl phenyl carbonylamino- methyl)-ethyl—108 —n-propyl— —NH—C(O)— cyclohexyl phenyl 109 —ethyl— —NH—SO₂—4-methyl-phenyl phenyl 111 —ethyl— —NH—C(O)— cyclohexyl phenyl 112—ethyl— —NH—C(O)— cyclopentyl phenyl 113 —n-butyl— —C(O)—N(cyclohexyl)—cyclohexyl 3-(phenyl- sulfonyl-amino)- phenyl 114 —n-butyl——C(O)—N(CH₃)— cyclohexyl 3-(phenyl- sulfonyl-amino)- phenyl 115—n-butyl— —NH—C(O)— cyclohexyl phenyl 116 —n-butyl— —NH—C(O)—cyclopentyl phenyl 121 —ethyl— —NH—C(O)— isopropyl phenyl 122 —ethyl——NH—C(O)— 1-ethyl-n-pentyl phenyl 123 —ethyl— —NH—C(O)— cyclopropylphenyl 127 1-(n-propyl)-n- —C(O)—N(ethyl)— cyclohexyl phenyl propyl— 1281-(n-propyl)-n- —C(O)—NH— cycloheptyl phenyl propyl— 129 1-(n-propyl)-n-—C(O)—NH— cyclohexyl phenyl propyl— 130 —ethyl— —NH—C(O)— cyclobutylphenyl 131 —ethyl— —NH—C(O)— 1-adamantyl phenyl 133 —n-butyl——C(O)—N(CH₃)— cyclohexyl 3-(benzyloxy- carbonyl- amino)-phenyl 134—ethyl— —NH—SO₂— n-propyl phenyl 135 —ethyl— —NH—SO₂— n-butyl phenyl 1371-(n-propyl)-n-butyl— —C(O)—NH— cycloheptyl phenyl 139 —ethyl— —NH—C(O)—2-phenyl- phenyl cyclopropyl 140 —ethyl— —NH—C(O)— cyclopentyl-ethyl—phenyl 141 —ethyl— —NH—C(O)— t-butyl phenyl 142 —ethyl— —NH—C(O)—n-nonyl phenyl 143 —n-propyl— —NH—C(O)— cyclopropyl phenyl 144—n-propyl— —NH—C(O)— cyclobutyl phenyl 148 1-(n-pentyl)-n- —C(O)—N(CH₃)—cyclohexyl phenyl propyl— 149 1-(n-pentyl)-n- —C(O)—NH— cyclohexylphenyl propyl— 150 1-(n-pentyl)-n- —C(O)—NH— cycloheptyl phenyl propyl—151 1-phenyl-n-propyl— —C(O)—N(CH₃)— cyclohexyl phenyl 1521-phenyl-n-butyl— —C(O)—N(CH₃)— cyclohexyl phenyl 154 —ethyl— —NH—C(O)—phenyl phenyl 155 —ethyl— —NH—C(O)— phenylethyl— phenyl 156 —ethyl——NH—C(O)— 4-t-butyl-phenyl phenyl 157 —ethyl— —NH—C(O)— 4-n-butyl-phenylphenyl 177 —n-propyl— —C(O)—N(CH₃)— cyclohexyl phenyl 178 —ethyl—C(O)—NH— cyclohexyl phenyl 179 —ethyl— —C(O)—N(isopropyl)— cyclohexylphenyl 180 —ethyl— —C(O)—N(cyclohexyl)— cyclohexyl phenyl 181 —ethyl——C(O)—N(isopropyl)— isopropyl phenyl 182 —ethyl— —NH—C(O)— 4-n-pentyl-phenyl cyclohexyl 183 —ethyl— —NH—C(O)— 4-n-heptyl phenyl 184 —ethyl——NH—C(O)— 4-t-butyl- phenyl cyclohexyl 189 —ethyl— —NH—C(O)—4-dimethylamino- phenyl phenyl 190 —ethyl— —NH—C(O)— isobutyl phenyl 191—ethyl— —NH—C(O)— 4-methyl- phenyl cyclohexyl 194 —ethyl— —NH—C(O)—1-(3-n-pentyl- phenyl bicyclo[2.2.2]- octyl) 195 —ethyl— —NH—C(O)—4-biphenyl phenyl 196 —ethyl— —NH—C(O)— 1-(1-(4- phenyl chlorophenyl)-cyclopentyl) 199 1-cyclohexyl-ethyl— —C(O)—N(CH₃)— cyclohexyl phenyl 2001-cyclohexyl-ethyl— —C(O)—N(isopropyl)— cyclohexyl phenyl 2011-isopropyl-ethyl— —C(O)—N(CH₃)— cyclohexyl phenyl 2021-isopropyl-ethyl— —C(O)—N(isopropyl)— cyclohexyl phenyl 205 —ethyl——NH—C(O)—NH— phenyl phenyl 206 —ethyl— —NH—C(O)—NH— 1-adamantyl phenyl207 —ethyl— —NH—C(O)— benzhydryl phenyl 208 1-(n-octyl)-n-propyl——C(O)—NH— cycloheptyl phenyl 210 1-(n-octyl)-n-propyl— —C(O)—N(CH₃)—cyclohexyl phenyl 214 —ethyl— —NH—C(S)—NH— 1-adamantyl phenyl 215—ethyl— —NH—C(O)—NH— cyclohexyl phenyl 216 —ethyl— —NH—C(O)—2-methoxy-phenyl phenyl 217 —ethyl— —NH—C(O)— 3-methoxy-phenyl phenyl218 —ethyl— —NH—C(O)— 2-methyl- phenyl cyclohexyl 219 —ethyl— —NH—C(O)—3-methoxy- phenyl cyclohexyl 220 —ethyl— —NH—C(O)O— isopropyl phenyl 221—ethyl— —C(O)—NH— 2-adamantyl phenyl 257 1-cyclohexyl-ethyl— —NH—C(O)O—t-butyl phenyl 258 1-phenyl-ethyl— —NH—C(O)O— t-butyl phenyl 288—n-butyl— —C(O)—N(CH₃)— cyclohexyl 3,5-dimethoxy- phenyl 2941-cyclohexyl-ethyl— —NH—C(O)— cyclohexyl phenyl 295 1-cyclohexyl-ethyl——NH—C(O)— cyclopentyl phenyl 297 1-(4-chloro-phenyl)- —C(O)—N(CH₃)—cyclohexyl phenyl n-propyl— 298 1-(4-methoxy- —C(O)—N(CH₃)— cyclohexylphenyl phenyl)-n-propyl— 299 1-phenyl-ethyl— —C(O)—NH— cyclohexyl phenyl300 1-cyclohexyl-ethyl— —C(O)—NH— cyclohexyl phenyl 3011-cyclohexyl-ethyl— —NH—C(O)— isopropyl phenyl 302 1-cyclohexyl-ethyl——NH—C(O)— 4-n-heptyl phenyl 303 1-cyclohexyl-ethyl— —NH—C(O)— 3-n-heptylphenyl 304 1-cyclohexyl-ethyl— —NH—C(O)— benzhydryl phenyl 3111-cyclohexyl-ethyl— —NH—C(O)— cyclopentyl- phenyl methyl— 3121-cyclohexyl-ethyl— —NH—C(O)— 1-adamantyl phenyl 313 1-cyclohexyl-ethyl——C(O)—NH— cyclohexyl 2-isopropyl- phenyl 314 1-cyclohexyl-ethyl——C(O)—NH— 2-adamantyl phenyl 317 1-cyclohexyl-ethyl— —NH—C(O)— t-butylphenyl 318 1-(n-propyl)-ethyl— —NH—C(O)O— t-butyl phenyl 3191-cyclohexyl-ethyl— —NH—C(O)— phenyl phenyl 341 1-phenyl-ethyl——NH—C(O)— 3-n-heptyl phenyl 342 1-phenyl-ethyl— —NH—C(O)— cyclohexylphenyl 343 1-(n-propyl)-ethyl —NH—C(O)— cyclohexyl phenyl 3461-(S)-cyclohexyl-n- —C(O)—N(CH₃)— cyclohexyl phenyl propyl— 365 —ethyl——C(O)—NH— 1-adamantyl phenyl 366 1-cyclohexyl-ethyl— —NH—C(O)—cyclopentyl-ethyl— phenyl 367 1-cyclohexyl-ethyl— —NH—C(O)O— t-butylphenyl 386 1-(R)-cyclohexyl-n- —C(O)—N(CH₃)— cyclohexyl phenyl propyl—388 1-cyclohexyl-ethyl NH—C(O) isopentyl phenyl 389 1-cyclohexyl-ethyl——NH—C(O)— isobutyl phenyl 390 1-cyclohexyl-ethyl— —NH—C(O)—1-(1-(4-chloro- phenyl phenyl)- cyclopentyl) 391 1-cyclohexyl-n-—NH—C(O)— cyclohexyl phenyl propyl— 392 1-cyclohexyl-n- —NH—C(O)—cyclopentyl phenyl propyl— 393 1-cyclohexyl-n- —NH—C(O)— cyclopentyl-phenyl propyl— methyl— 394 —ethyl— —NH—C(O)O— t-butyl 3-(phenyl-sulfonyl-amino)- phenyl 400 1-cyclohexyl-ethyl— —C(O)—NH— 2- phenyl(bicyclo[2.2.1] heptyl) 401 1-isopropyl-ethyl— —C(O)—NH— cyclohexylphenyl 402 1-isopropyl-ethyl— —C(O)—NH— 2-adamantyl phenyl 403—n-propyl— —NH— cyclohexyl phenyl 420 1-(4-biphenyl)-n- —C(O)—N(CH₃)—cyclohexyl phenyl propyl— 421 1-(4-methyl- —C(O)—N(CH₃)— cyclohexylphenyl phenyl)-n-propyl— 425 —ethyl— —N(CH₃)—C(O)O— t-butyl phenyl 426—ethyl— —N(CH₃)—C(O)— cyclohexyl phenyl 427 —ethyl— —NH— cyclohexyl-phenyl methyl— 428 —n-propyl— —N(CH₃)— cyclohexyl phenyl 429 —ethyl——N(CH₃)— cyclohexyl phenyl 444 1-(R)-isopropyl-n- —C(O)—N(CH₃)—cyclohexyl phenyl propyl— 450 1-(S)-isopropyl-n- —C(O)—N(CH₃)—cyclohexyl phenyl propyl— 452 1-(1-piperidinyl- —C(O)— N-piperidinylphenyl carbonyl-n-propyl)- n-propyl— 465 —ethyl— —C(O)—NH— 2-adamantyl2,6-dimethoxy- phenyl 466 —ethyl— —C(O)—NH— 2-adamantyl 2-isopropyl-phenyl 484 1-(S)-cyclohexyl- —NH—C(O)— cyclohexyl phenyl ethyl— 4851-(R)-cyclohexyl- —NH—C(O)— cyclohexyl phenyl ethyl— 4861-(S)-methyl-ethyl— —NH—C(O)— cyclohexyl phenyl 495 1-(R)-methyl-ethyl——NH—C(O)— cyclohexyl phenyl 504 1-(2-methyl- —C(O)— 2-methyl- phenylpiperidinyl- piperidinyl carbonyl-n-propyl)- n-propyl— 511 —ethyl——C(O)—NH— trans-2-methyl- phenyl cyclohexyl- 528 1-(S)-isopropyl-—NH—C(O)— cyclohexyl phenyl ethyl— 529 —ethyl— —C(O)—NH— 2-adamantyl2,6-difluoro- phenyl 532 1-(4-methyl- —C(O)— 4-methyl- phenylpiperidinyl- piperidinyl carbonyl-n-propyl)- n-propyl— 5531-(S)-isopropyl- —NH—C(O)— 1-adamantyl phenyl ethyl— 554 1-(S)-n-propyl-—NH—C(O)— cyclohexyl phenyl ethyl— 555 1-(S)-n-propyl- —NH—C(O)—1-adamantyl phenyl ethyl— 557 1-(R)-hydroxy- —C(O)—N(CH₃)— cyclohexylphenyl methyl-n-propyl— 558 1-(S)-hydroxy- —C(O)—N(CH₃)— cyclohexylphenyl methyl)-n-propyl— 561 1-(R)-isopropyl- —NH—C(O)— cyclohexylphenyl ethyl— 562 1-(R)-isopropyl- —NH—C(O)— 1-adamantyl phenyl ethyl—563 1-(R)-isopropyl- —NH—C(O)— isobutyl phenyl ethyl— 5641-(R)-isopropyl- —NH—C(O)— isopentyl phenyl ethyl— 601 1-(R)-n-propyl-—NH—C(O)— cyclohexyl phenyl ethyl— 602 1-(R)-n-propyl- —NH—C(O)—1-adamantyl phenyl ethyl— 603 1-(R)-n-propyl- —NH—C(O)— isopentyl phenylethyl— 614 1-(R)-(4-hydroxy- —NH—C(O)— cyclohexyl phenyl benzyl)-ethyl—615 1-(R)-(4-hydroxy- —NH—C(O)— isopentyl phenyl benzyl)-ethyl— 6161-(S)-(4-hydroxy- —NH—C(O)— cyclohexyl phenyl benzyl)-ethyl— 618 —ethyl——C(O)—N(CH₃)— 2-adamantyl phenyl 619 1-(4-tetrahydro- —C(O)—N(CH₃)—cyclohexyl phenyl pyranyl)-n-propyl— 632 1-(4-hydroxy- —C(O)—N(CH₃)—cyclohexyl phenyl cyclohexyl)-n- propyl— 633 1-(R)-cyclohexyl-n-—C(O)—N(CH₃)— 4-tetrahydro- phenyl propyl— pyranyl 6341-(S)-(N-methyl-N- —C(O)—N(CH₃)— cyclohexyl phenyl cyclohexyl-aminocarbonyl)-n- propyl— 636 2-(S)-cyclohexyl- —NH—C(O)— cyclohexylphenyl ethyl— 637 2-(R)-cyclohexyl- —NH—C(O)— cyclohexyl phenyl ethyl—638 1-(S)-cyclohexyl-n- —C(O)—N(CH₃)— 4-tetrahydro- phenyl propyl—pyranyl 639 1-(R)-cyclohexyl-n- —C(O)—N(CH₃)— 4-hydroxy- phenyl propyl—cyclohexyl 709 1-(S)-tetrahydro- —C(O)—N(CH₃)— cyclohexyl phenylpyranyl-n-propyl— 710 1-(S)-cyclohexyl-n- —C(O)—N(CH₃)— 1,4-dioxa-phenyl propyl— spiro[4.5]dec-8-yl 711 1-(S)-cyclohexyl-n- —C(O)—N(CH₃)—1-4-oxo- phenyl propyl— cyclohexyl 712 1-(S)-cyclohexyl-n- —C(O)—N(CH₃)—4-hydroxy- phenyl propyl— cyclohexyl 714 1-(S)-cyclohexyl-n-—C(O)—N(CH₃)— 4-carboxy- phenyl propyl— cyclohexyl 7281-(S)-cyclohexyl-n- —C(O)—N(CH₃)— 4-(1-isopropyl)- phenyl propyl—piperidinyl 730 1-(S)-(1,4-dioxa- —C(O)—N(CH₃)— cyclohexyl phenylspiro[4.5]dec-8-yl)- n-propyl— 731 1-(S)-(cis-4- —C(O)—N(CH₃)—cyclohexyl phenyl hydroxy- cyclohexyl)-n- propyl— 732 1-(S)-(4-oxo-—C(O)—N(CH₃)— cyclohexyl phenyl cyclohexyl)-n- propyl— 7361-(S)-cyclohexyl-n- —C(O)—N(hydroxyethyl)— cyclohexyl phenyl propyl— 7371-(S)-cyclohexyl-n- —C(O)—N(CH₃)— 4-ethoxy- phenyl propyl— carbonyl-cyclohexyl 738 1-(dimethyl)-n- —C(O)—N(CH₃)— cyclohexyl phenyl propyl—739 1-(S)-cyclohexyl-n- —C(O)—N(CH₃)— cis-(4-carboxy)- phenyl propyl—cyclohexyl 740 1-(S)-cyclohexyl-n- —C(O)—N(CH₃)— trans-(4-carboxy)-phenyl propyl— cyclohexyl 741 1-(S)-cyclohexyl-n- —C(O)—N(CH₃)—1-carboxy- phenyl propyl— cyclohexyl 742 1-(S)-(4- —C(O)—N(CH₃)—4-(ethoxy- phenyl tetrahydropyranyl)- carbonyl)- n-propyl— cyclohexyl743 1-(S)-(4- —C(O)—N(CH₃)— 4-carboxy- phenyl tetrahydropyranyl)-cycohexyl n-propyl— 744 1-(S)-(4- —C(O)—N(CH₃)— cis-(4-methoxy- phenyltetrahydropyranyl)- carbonyl)- n-propyl— cyclohexyl 745 1-(S)-(4-—C(O)—N(CH₃)— cis-(4-carboxy)- phenyl tetrahydropyranyl)- cyclohexyln-propyl— 746 1-(S)-(4- —C(O)—N(CH₃)— trans-(4-carboxy)- phenyltetrahydropyranyl)- cyclohexyl n-propyl— 747 1-(S)-(4- —C(O)—NH—trans-(4-methoxy- phenyl tetrahydropyranyl)- carbonyl)- n-propyl—cyclohexyl 748 1-(S)-(4- —C(O)—N(CH₃)— cis-(4-carboxy)- phenyltetrahydropyranyl)- cyclohexyl n-propyl— 749 1-(S)-(cyclohexyl)-—C(O)—N(hydroxyethyl)— cis-(4-carboxy)- phenyl n-propyl— cyclohexyl 7501-(S)-(4- —C(O)—N(hydroxyethyl)— cis-(4-carboxy)- phenyltetrahydropyranyl)- cyclohexyl n-propyl— 751 1-(S)-(4-—C(O)—N(benzyloxy- cis-(4-carboxy)- phenyl tetrahydropyranyl)- ethyl)—cyclohexyl n-propyl— 752 1-(S)-(cyclohexyl)- —C(O)—N(CH₃)—4-(carboxy)-n- phenyl n-propyl— butyl 760 1-(S)-(cyclohexyl)-—C(O)—N(CH₃)— 1-cis-(4- phenyl n-propyl benzyloxy- carbonyl- cyclohexyl)761 1-(S)-(cyclohexyl)- —C(O)—N(CH₃)— 1-cis-(4-methoxy- phenyl n-propylcarbonyl- cyclohexyl) 762 1-(S)-(cyclohexyl)- —C(O)—N(CH₂CH₂OH)—1-cis-(4-methoxy- phenyl n-propyl carbonyl- cyclohexyl) 7631-(S)-(cyclohexyl)- —C(O)—N(CH₃)— 1-cis-(4-ethoxy- phenyl n-propylcarbonyl- cyclohexyl) 764 1-(S)-(cyclohexyl)- —C(O)—N(CH₃)—1-cis-(4-amino- phenyl n-propyl carbonyl- cyclohexyl) 7651-(S)-(cyclohexyl)- —C(O)—N(CH₃)— 1-cis-(4- phenyl n-propyl methylamino-carbonyl- cyclohexyl) 766 1-(S)-(cyclohexyl)- —C(O)—N(CH₃)—1-(4-carboxy- phenyl n-propyl phenyl) 767 1-(S)-(cyclohexyl)-—C(O)—N(CH₃)— carboxy-methyl— phenyl n-propyl 768 1-(S)-(cyclohexyl)-—C(O)—N(cyclohexyl)— carboxy-methyl— phenyl n-propyl 7691-(S)-(cyclohexyl)- —C(O)—N(CH₃)— 1-(4-cyano- phenyl n-propylcyclohexyl) 770 1-(S)-(cyclohexyl)- —C(O)—N(CH₃)— 1-(4-(5-tetrazolyl)-phenyl n-propyl cyclohexyl) 771 1-(S)-(4-tetrahydro- —C(O)—NH—1-(S)-(1-carboxyl- phenyl pyranyl)-n-propyl 2-hydroxy-ethyl) 7731-(S)-(4-tetrahydro- —C(O)—NH— 1-(R)-(1-carboxyl- phenylpyranyl)-n-propyl 2-hydroxy-ethyl) 774 1-(S)-(4-tetrahydro- —C(O)—NH—1-(R)-(1-carboxyl- phenyl pyranyl)-n-propyl 2-t-butoxy-ethyl) 7751-(S)-(cyclohexyl)- —C(O)—N(CH₃)— 3-(methoxy- phenyl n-propylcarbonyl-methyl)- benzyl 776 1-(S)-(cyclohexyl)- —C(O)—N(CH₃)—1-cis-(3-carboxy)- phenyl n-propyl cyclohexyl 777 1-(S)-(cyclohexyl)-—C(O)—N(CH₃)— 1-cis-(3-methoxy- phenyl n-propyl carbonyl)- cyclohexyl778 1-(S)-(cyclohexyl)- —C(O)—N(CH₃)— 3-(carboxy- phenyl n-propylmethyl)-benzyl 779 1-(S)-(cyclohexyl)- —C(O)—N(CH₃)— 1-(R)-(1-methoxy-phenyl n-propyl carbonyl-2- benzyloxy-ethyl) 780 1-(S)-(cyclohexyl)-—C(O)—N(CH₃)— 1-(S)-(1-methoxy- phenyl n-propyl carbonyl-2-benzyloxy-ethyl) 781 1-(S)-(cyclohexyl)- —C(O)—N(CH₃)— 1-(S)-(1-carboxy-phenyl n-propyl 2-benzyloxy-ethyl) 782 1-(S)-(4-tetrahydro- —C(O)—NH—1-(S)-(1-carboxy- phenyl pyranyl)-n-propyl 2-benzyloxy-ethyl) 7831-(S)-(4-tetrahydro- —C(O)—N(CH₃)— 1-(R)-(1-methoxy- phenylpyranyl)-n-propyl carbonyl-2- benzyloxy-ethyl) 784 1-(S)-(4-tetrahydro-—C(O)—N(CH₃)— 1-(R)-(1-carboxy- phenyl pyranyl)-n-propyl2-benzyloxy-ethyl) 785 1-(S)-(4-tetrahydro- —C(O)—NH— 1-(S)-(1-methoxy-phenyl pyranyl)-n-propyl carbonyl-2- benzyloxy-ethyl) 7861-(S)-(4-tetrahydro- —C(O)—N(CH₃)— 1-(S)-(1-methoxy- phenylpyranyl)-n-propyl carbonyl-2- benzyloxy-ethyl) 787 1-(S)-(cyclohexyl-n-—C(O)—N(cyclohexyl)— 5-tetrazolyl- phenyl propyl) methyl— 7881-(S)-(cyclohexyl)- —C(O)—N(cyclohexyl)— 2-imidazolyl- phenyl n-propylmethyl— 789 1-(S)-(cyclohexyl)- —C(O)—N(cyclohexyl)— 4-pyridyl-methyl—phenyl n-propyl 790 1-(S)-(cyclohexyl)- —C(O)—N(cyclohexyl)—3-(1,2,4-triazolyl)- phenyl n-propyl methyl— 791 1-(S)-(cyclohexyl)-—C(O)— 1-(S)-(2-carboxy- phenyl n-propyl pyrrolidinyl) 7921-(S)-(cyclohexyl)- —C(O)— 1-(S)-(2-methoxy- phenyl n-propyl carbonyl-piperidinyl) 793 1-(S)-(cyclohexyl)- —C(O)— 1-(S)-(2-methoxy- phenyln-propyl carbonyl- octahydroindolyl) 794 1-(S)-(cyclohexyl)- —C(O)—1-(S)-(2-carboxy- phenyl n-propyl piperidinyl) 795 1-(S)-(cyclohexyl)-—C(O)— 1-(S)-(2-carboxy- phenyl n-propyl octahydroindolyl) 7961-(S)-(cyclohexyl)- —C(O)—N(cyclohexyl)— 5-imidazolyl- phenyl n-propylmethyl— 797 1-(S)-(cyclohexyl)- —C(O)—N(cyclohexyl)— 2R-(3R,4S,5R-phenyl n-propyl tri(methyl- carbonyloxy)-6R- (methyl- carbonyloxy-methyl)- tetrahydro- pyranyl)oxy-ethyl— 798 1-(S)-(cyclohexyl)-—C(O)—N(cyclohexyl)— 2R-(3S,4S,5R- phenyl n-propyl trihydroxy-6R-(hydroxy-methyl)- tetrahydro- pyranyl)oxy-ethyl— 799 1-(S)-(cyclohexyl)-—C(O)—N(cyclohexyl)— 3-(2R- phenyl n-propyl (3S,4S,5R,6R- tetrahydroxy-tetrahydro- pyranyl)-methoxy- carbonyl-amino)- n-propyl—

TABLE 4 Compounds of Formula (I)

ID No A¹ Q¹ R² R³ 37 —ethyl— —C(O)—N(CH₃)— cyclohexyl 3-(6-fluoro-benzo[d]isoxazole 226 1-cyclohexyl-n- —C(O)—N(CH₃)— cyclohexyl4-methoxy-phenyl propyl— 227 1-cyclohexyl-n- —C(O)—N(CH₃)— cyclohexyl2-methoxy-phenyl propyl— 487 —ethyl— —NH—C(O)— cyclohexyl2-methoxy-phenyl 488 —ethyl— —NH—C(O)— 1-(amino- 2-methoxy-phenylcarbonyl)- cyclopropyl 490 —ethyl— —NH—C(O)— amino-methyl—2-methoxy-phenyl 491 —ethyl— —NH—C(O)— 4-(1-(methyl- 2-methoxy-phenylcarbonyl)- piperidinyl) 493 —ethyl— —NH—C(O)— amino-ethyl—2-methoxy-phenyl 494 —ethyl— —NH—C(O)— 3-amino-n- 2-methoxy-phenylpropyl 506 1-(S)- —C(O)—N(CH₃)— cyclohexyl 2-methoxy-phenylcyclohexyl-n- propyl— 515 —ethyl— —NH—C(O)— cyclohexyl phenyl 530 1-(R)-—C(O)—N(CH₃)— cyclohexyl 2-methoxy-phenyl cyclohexyl-n- propyl— 535—ethyl— —NH—C(O)— cyclohexyl 2-fluoro-phenyl 536 —ethyl— —NH—C(O)—cyclohexyl 2-chloro-phenyl 537 —ethyl— —NH—C(O)— cyclohexyl2-methyl-phenyl 538 —ethyl— —NH—C(O)— cyclohexyl 2-hydroxy-phenyl 539—ethyl— —NH—C(O)— cyclohexyl 2-(methyl-sulfonyl- amino)-phenyl 540—ethyl— —NH—C(O)— cyclohexyl 2-methylthio-phenyl 541 —ethyl— —NH—C(O)—cyclohexyl 2-(methyl-carbonyl- amino)-phenyl 542 —ethyl— —NH—C(O)—cyclohexyl 2-(t-butyl-amino- sulfonyl)-phenyl 543 —ethyl— —NH—C(O)—cyclohexyl 2-(amino-carbonyl)- phenyl 544 —ethyl— —NH—C(O)— cyclohexyl2-biphenyl 545 —ethyl— —NH—C(O)— cyclohexyl 2-fluoro-6-methoxy- phenyl556 —ethyl— —C(O)—NH— 2-adamantyl 2-methoxy-phenyl 567 —ethyl— —NH—C(O)—3-cyano-phenyl 5-pyrimidinyl 568 —ethyl— —NH—C(O)— 3-cyano-phenyln-penten-1-yl 569 —ethyl— —NH—C(O)— n-propyl 5-pyrimidinyl 570 —ethyl——NH—C(O)— n-propyl 4-pyridyl 571 —ethyl— —NH—C(O)— n-propyln-penten-1-yl 572 —ethyl— —NH—C(O)— t-butyl 5-pyrimidinyl 573 —ethyl——NH—C(O)— t-butyl 4-pyridyl 574 —ethyl— —NH—C(O)— t-butyl n-penten-1-yl575 —ethyl— —NH—C(O)— cyclohexyl 5-pyrimidinyl 576 —ethyl— —NH—C(O)—cyclohexyl 4-pyridyl 577 —ethyl— —NH—C(O)— cyclohexyl n-penten-1-yl 578—ethyl— —NH—C(O)— cyclopentyl- phenyl methyl— 580 —ethyl— —NH—C(O)—cyclopentyl- n-penten-1-yl methyl— 582 —ethyl— —NH—C(O)— cyclopentyl-3-(methyl-carbonyl)- methyl— phenyl 583 —ethyl— —NH—C(O)— cyclopentyl-3-hydroxymethyl- methyl— phenyl 584 —ethyl— —NH—C(O)— cyclopentyl-3-trifluoromethyl- methyl— phenyl 586 —ethyl— —NH—C(O)— 3-(2,5-dimethyl-phenyl furyl) 587 —ethyl— —NH—C(O)— 3-(2,5-dimethyl- n-penten-1-ylfuryl) 588 —ethyl— —NH—C(O)— 3-(2,5-dimethyl- 3-(methyl-carbonyl)-furyl) phenyl 589 —ethyl— —NH—C(O)— 3-(2,5-dimethyl- 3-hydroxymethyl-furyl) phenyl 590 —ethyl— —NH—C(O)— 3-(2,5-dimethyl- 3-trifluoromethyl-furyl) phenyl 591 —ethyl— —NH—C(O)— 4-(methyl- phenyl carbonyl-amino)-phenyl 592 —ethyl— —NH—C(O)— 4-(methyl- n-penten-1-yl carbonyl-amino)-phenyl 593 —ethyl— —NH—C(O)— 4-(methyl- 3-hydroxymethyl-carbonyl- phenyl amino)-phenyl 594 —ethyl— —NH—C(O)— 4-(methyl-3-trifluoromethyl- carbonyl- phenyl amino)-phenyl 595 —ethyl— —NH—C(O)—benzyl phenyl 596 —ethyl— —NH—C(O)— benzyl n-penten-1-yl 598 —ethyl——NH—C(O)— benzyl 3-(methyl-carbonyl)- phenyl 599 —ethyl— —NH—C(O)—benzyl 3-hydroxymethyl- phenyl 600 —ethyl— —NH—C(O)— benzyl3-trifluoromethyl- phenyl 610 —ethyl— —C(O)—NH— cyclohexyl2-methoxy-phenyl 623 —ethyl— —NH—C(O)— cyclohexyl 4-fluoro-phenyl 624—ethyl— —NH—C(O)— cyclohexyl 4-fluoro-phenyl 625 —ethyl— —NH—C(O)—cyclohexyl 3-chloro-phenyl 626 —ethyl— —NH—C(O)— cyclohexyl4-chloro-phenyl 627 —ethyl— —NH—C(O)— cyclohexyl 3-methyl-phenyl 628—ethyl— —NH—C(O)— cyclohexyl 4-methyl-phenyl 629 —ethyl— —NH—C(O)—cyclohexyl 2,6-difluoro-phenyl 630 —ethyl— —NH—C(O)— cyclohexyl2-methoxy-5-methyl- phenyl 631 —ethyl— —NH—C(O)— cyclohexyl2-methoxy-5-fluoro- phenyl 635 —ethyl— —C(O)—NH— 2-adamantyl2-fluoro-phenyl 642 —ethyl— —NH—C(O)— cyclobutyl 2-fluoro-phenyl 643—ethyl— —NH—C(O)— cyclopentyl 2-fluoro-phenyl 644 —ethyl— —NH—C(O)—1-adamantyl 2-fluoro-phenyl 645 —ethyl— —NH—C(O)— n-propyl2-fluoro-phenyl 646 —ethyl— —NH—C(O)— t-butyl 2-fluoro-phenyl 647—ethyl— —NH—C(O)— isopentyl 2-fluoro-phenyl 648 —ethyl— —NH—C(O)—3-n-heptyl 2-fluoro-phenyl 649 —ethyl— —NH—C(O)— cyclobutyl2-chloro-phenyl 650 —ethyl— —NH—C(O)— cyclopentyl 2-chloro-phenyl 651—ethyl— —NH—C(O)— 1-adamantyl 2-chloro-phenyl 652 —ethyl— —NH—C(O)—n-propyl 2-chloro-phenyl 653 —ethyl— —NH—C(O)— t-butyl 2-chloro-phenyl654 —ethyl— —NH—C(O)— isopentyl 2-chloro-phenyl 655 —ethyl— —NH—C(O)—3-n-heptyl 2-chloro-phenyl 656 —ethyl— —NH—C(O)— cyclobutyl2-methyl-phenyl 657 —ethyl— —NH—C(O)— cyclopentyl 2-methyl-phenyl 658—ethyl— —NH—C(O)— 1-adamantyl 2-methyl-phenyl 659 —ethyl— —NH—C(O)—n-propyl 2-methyl-phenyl 660 —ethyl— —NH—C(O)— t-butyl 2-methyl-phenyl661 —ethyl— —NH—C(O)— isopentyl 2-methyl-phenyl 662 —ethyl— —NH—C(O)—3-n-heptyl 2-methyl-phenyl 663 —ethyl— —NH—C(O)— cyclobutyl 2-naphthyl664 —ethyl— —NH—C(O)— cyclopentyl 2-naphthyl 665 —ethyl— —NH—C(O)—1-adamantyl 2-naphthyl 666 —ethyl— —NH—C(O)— n-propyl 2-naphthyl 667—ethyl— —NH—C(O)— t-butyl 2-naphthyl 668 —ethyl— —NH—C(O)— isopentyl2-naphthyl 669 —ethyl— —NH—C(O)— 3-n-heptyl 2-naphthyl 670 —ethyl——NH—C(O)— cyclobutyl 3-quinolinyl 671 —ethyl— —NH—C(O)— cyclopentyl3-quinolinyl 672 —ethyl— —NH—C(O)— 1-adamantyl 3-quinolinyl 673 —ethyl——NH—C(O)— n-propyl 3-quinolinyl 674 —ethyl— —NH—C(O)— t-butyl3-quinolinyl 675 —ethyl— —NH—C(O)— isopentyl 3-quinolinyl 676 —ethyl——NH—C(O)— 3-n-heptyl 3-quinolinyl 678 —ethyl— —NH—C(O)— 3,3,3-trifluoro-2-methyl-phenyl n-propyl 679 —ethyl— —NH—C(O)— 3,3,3-trifluoro-2-methyl-phenyl isobutyl 680 —ethyl— —NH—C(O)— 3,3,3-trifluoro-2-fluoro-phenyl n-propyl 681 —ethyl— —NH—C(O)— 3,3,3-trifluoro-2-fluoro-phenyl isobutyl 682 —ethyl— —NH—C(O)— 3,3,3-trifluoro-2-chloro-phenyl n-propyl 683 —ethyl— —NH—C(O)— 3,3,3-trifluoro-2-chloro-phenyl isobutyl 684 —ethyl— —NH—C(O)— 3,3,3-trifluoro- phenyln-propyl 685 —ethyl— —NH—C(O)— 3,3,3-trifluoro- phenyl isobutyl 686—ethyl— —NH—C(O)— 3,3,3-trifluoro- 2-naphthyl n-propyl 687 —ethyl——NH—C(O)— 4-tetrahydro- 2-fluoro-phenyl pyranyl 688 —ethyl— —NH—C(O)—4-trifluoro- 2-fluoro-phenyl methyl- cyclohexyl 689 —ethyl— —NH—C(O)—4-tetrahydro- 2-chloro-phenyl pyranyl 690 —ethyl— —NH—C(O)— 4-trifluoro-2-chloro-phenyl methyl- cyclohexyl 691 —ethyl— —NH—C(O)— 4-(1-2-chloro-phenyl methylcarbonyl)- piperidinyl 692 —ethyl— —NH—C(O)—1-(3-methoxy- 2-chloro-phenyl cyclohexyl) 693 —ethyl— —NH—C(O)—4-tetrahydro- 2-methyl-phenyl pyranyl 694 —ethyl— —NH—C(O)— 4-trifluoro-2-methyl-phenyl methyl- cyclohexyl 695 —ethyl— —NH—C(O)— 4-(1-2-methyl-phenyl methylcarbonyl)- piperidinyl 696 —ethyl— —NH—C(O)—3-methoxy- 2-methyl-phenyl cyclohexyl 697 —ethyl— —NH—C(O)—4-tetrahydro- 2-methoxy-phenyl pyranyl 698 —ethyl— —NH—C(O)—4-trifluoro- 2-methoxy-phenyl methyl- cyclohexyl 699 —ethyl— —NH—C(O)—4-tetrahydro- 2-fluoro-6-methoxy- pyranyl phenyl 700 —ethyl— —NH—C(O)—4-trifluoro- 2-fluoro-6-methoxy- methyl- phenyl cyclohexyl 701 —ethyl——NH—C(O)— 4-trifluoro- phenyl methyl- cyclohexyl 702 —ethyl— —NH—C(O)—4-(1- phenyl methylcarbonyl)- piperidinyl 703 —ethyl— —NH—C(O)—3-methoxy- phenyl cyclohexyl 704 —ethyl— —NH—C(O)— 4-trifluoro-1-cyclohexenyl methyl- cyclohexyl 705 —ethyl— —NH—C(O)— 4-(1-1-cyclohexenyl methylcarbonyl)- piperidinyl 706 —ethyl— —NH—C(O)—3-methoxy- 1-cyclopentenyl cyclohexyl 707 —ethyl— —NH—C(O)— 4-trifluoro-1-cyclopentenyl methyl- cyclohexyl 716 1-(S)- —C(O)—N(CH₃)— 4-(2-phenyl-2-methoxy-phenyl cyclohexyl-n- thiazolyl)- propyl— methyl— 717 1-(S)-—C(O)—N(CH₃)— 4-(1-phenyl- 2-methoxy-phenyl cyclohexyl-n- pyrazolyl)-propyl— methyl— 718 1-(S)- —C(O)—N(CH₃)— 5-(3-methyl- 2-methoxy-phenylcyclohexyl-n- isoxazolyl)- propyl— methyl— 719 1-(S)- —C(O)—N(CH₃)—3-(5-phenyl- 2-methoxy-phenyl cyclohexyl-n- isoxazolyl)- propyl— methyl—720 1-(S)- —C(O)—N(CH₃)— 2-cyanoethyl— 2-methoxy-phenyl cyclohexyl-n-propyl— 721 1-(S)- —C(O)—N(CH₃)— phenylethyl— 2-methoxy-phenylcyclohexyl-n- propyl— 722 1-(S)- —C(O)—N(CH₃)— 4-(2-phenyl-2-fluoro-phenyl cyclohexyl-n- thiazolyl)- propyl— methyl— 723 1-(S)-—C(O)—N(CH₃)— 5-(3-methyl- 2-fluoro-phenyl cyclohexyl-n- isoxazolyl)-propyl— methyl— 724 1-(S)- —C(O)—N(CH₃)— 3-(5-phenyl- 2-fluoro-phenylcyclohexyl-n- isoxazolyl)- propyl— methyl— 725 1-(S)- —C(O)—N(CH₃)—2-cyanoethyl— 2-fluoro-phenyl cyclohexyl-n- propyl— 726 1-(S)-—C(O)—N(CH₃)— 4-methyl- 2-fluoro-phenyl cyclohexyl-n- piperidinylpropyl— 727 1-(S)- —C(O)—N(CH₃)— phenylethyl— 2-fluoro-phenylcyclohexyl-n- propyl—

TABLE 5 Compound of formula (I)

ID No. R¹⁰ A¹ Q¹ R² R³ 617 H —ethyl— —C(O)—NH— 2- 2-methoxy- adamantylphenyl 620 F —ethyl— —C(O)—NH— 2- 2-methoxy- adamantyl phenyl

TABLE 6 Compounds of Formula (I)

ID No. R² (L¹)_(b) R³ 32 cyclohexyl —C(OH)— phenyl 36 cyclohexyl —CH₂—phenyl

TABLE 7 Compounds of formula (III)

ID No R⁶ R⁷ L³ R⁸ 44 n-propyl —phenyl— —3-NH—C(O)— cyclohexyl 49n-propyl —phenyl— —3-N(cyclohexyl)-C(O)O— benzyl 53 n-propyl —phenyl——3-NH— cyclohexyl 55 n-propyl —phenyl— —3-NH— cyclohexyl-methyl— 56n-propyl —phenyl— —3-N(CN)— cyclohexyl-methyl— 60 n-propyl —phenyl——3-NH—C(O)— phenyl 61 n-propyl —phenyl— —3-NH—SO₂— phenyl 67 n-propyl—phenyl— —3-NH—C(O)O— benzyl 95 4-hydroxy-n- —phenyl— —3-NH—cyclohexyl-methyl— butyl 126 4-hydroxy-n- —phenyl— —3-NH—SO₂— phenylbutyl 203 n-propyl —CH₂-phenyl— —3-NH—SO₂— phenyl 225 n-propyl—phenyl-3-CH₂— —NH—SO₂— phenyl 237 n-propyl —phenyl— —3-NH—SO₂— methyl238 n-propyl —phenyl— —3-NH—SO₂— isopropyl 239 n-propyl —phenyl——3-NH—SO₂— n-butyl 240 n-propyl —phenyl— —3-NH—SO₂— 3-thienyl 241n-propyl —phenyl— —3-NH—SO₂— 2-thienyl 242 n-propyl —phenyl— —3-NH—SO₂—4-(3,5-dimethyl- isoxazolyl) 243 n-propyl —phenyl— —3-NH—SO₂—2,4,6-trimethyl- phenyl 244 n-propyl —phenyl— —3-NH—SO₂— 2-naphthyl 245n-propyl —phenyl— —3-NH—SO₂— 3-benzothienyl 246 n-propyl —phenyl——3-NH—SO₂— 4-(methyl-carbonyl- amino)-phenyl 247 n-propyl —phenyl——3-NH—SO₂— 4-benzo[2,3,1]- thiadiazolyl 248 n-propyl —phenyl— —3-NH—SO₂—2,5-dimethoxy-phenyl 249 n-propyl —phenyl— —3-NH—SO₂—3,4-dimethoxy-phenyl 250 n-propyl —phenyl— —3-NH—SO₂—2-(methyl-sulfonyl)- phenyl 251 n-propyl —phenyl— —3-NH—SO₂—2-(5-(2-pyridyl)- thienyl) 252 n-propyl —phenyl— —3-NH—SO₂—3-trifluoromethoxy- phenyl 253 n-propyl —phenyl— —3-NH—SO₂—1-(5-(dimethyl- amino)-naphthyl) 254 n-propyl —phenyl— —3-NH—SO₂—2-(5-(3-(2-methyl- thiazolyl)-thienyl)) 255 n-propyl —phenyl— —3-NH—SO₂—2-(5-(3-(5-trifluoro- methyl)-isoxazolyl)- thienyl) 269 n-propyl—phenyl— —3-NH—SO₂— benzyl 270 n-propyl —phenyl— —3-NH—SO₂—3-cyano-phenyl 271 n-propyl —phenyl— —3-NH—SO₂— 3-methoxy-phenyl 272n-propyl —phenyl— —3-NH—SO₂— 4-methoxy-phenyl 273 n-propyl —phenyl——3-NH—SO₂— 2-methoxy-4-methyl- phenyl 274 n-propyl —phenyl— —3-NH—SO₂—1-naphthyl 275 n-propyl —phenyl— —3-NH—SO₂— 6-(2,3-dihydro-benzo[1,4]dioxanyl) 276 n-propyl —phenyl— —3-NH—SO₂— 3-(2-methoxy-carbonyl)-thienyl) 277 n-propyl —phenyl— —3-NH—SO₂— 2-trifluoromethyl-phenyl 278 n-propyl —phenyl— —3-NH—SO₂— 2-(5-(5-isoxazolyl)- thienyl))279 n-propyl —phenyl— —3-NH—SO₂— 5-carboxy-2- methoxy-phenyl 280n-propyl —phenyl— —3-NH—SO₂— 4-biphenyl 281 n-propyl —phenyl— —3-NH—SO₂—1-naphthyl-ethyl— 282 n-propyl —phenyl— —3-NH—SO₂— 3-bromo-phenyl 283n-propyl —phenyl— —3-NH—SO₂— 4-trifluoromethoxy- phenyl 284 n-propyl—phenyl— —3-NH—SO₂— 2-(5-bromo-thienyl) 285 n-propyl —phenyl— —3-NH—SO₂—2-(4-phenyl-sulfonyl)- thienyl 296 n-propyl —phenyl-3-CH₂— —NH— benzyl305 n-propyl —phenyl-3-CH₂— —NH— 3-hydroxy-benzyl 335 n-propyl—phenyl-3-CH₂— —NH— 2-methoxy-benzyl 340 n-propyl —phenyl-3-CH₂— —NH—2,6-dimethoxy-benzyl 344 n-propyl —phenyl-3-CH₂— —NH—2,4,6-trimethyl-benzyl 355 5-hydroxy-n- —phenyl— —3-NH—SO₂— 2-methoxy-4-pentyl methyl-phenyl 380 5-hydroxy-n- —phenyl— —3-NH—SO₂— phenyl pentyl383 5-hydroxy-n- —phenyl— —3-NH—SO₂— 2,4,6-trimethyl- pentyl phenyl 423n-propyl —phenyl— —3-C(O)—NH— 2,4,6-trimethyl-benzyl 430 n-propyl—phenyl-3-CH₂— —NH— phenyl-n-propyl— 431 n-propyl —phenyl-3-CH₂— —NH—phenylethyl— 464 n-propyl —phenyl-3-CH₂— —N(CH₃)— 2,4,6-trimethyl-benzyl500 n-propyl —phenyl— —3-NH— 2,4,6-trimethyl-benzyl 501 n-propyl—phenyl— —3-NH— 2,6-dimethoxy-benzyl 502 n-propyl —phenyl— —3-NH—4-methoxy-benzyl 507 n-propyl —phenyl— —3-NH— benzyl 533 n-propyl—phenyl-3-CH₂— —NH—C(O)— 2,4,6-trimethyl- phenyl 729 n-propyl —phenyl——3-NH— 4-methyl-benzyl 755 n-propyl —phenyl— —3-NH—C(O)— 3-(N-methyl-N-cyclohexyl-amino- carbonyl)-n-propyl

TABLE 8 Compounds of formula (III)

ID No R⁶ (L²)_(d) R⁷ L³ R⁸ 345 n-propyl —S— —phenyl— —3-NH—SO₂— phenyl385 n-propyl absent —phenyl-2-CH₂—CH₂— —NH—SO₂— phenyl 387 n-propyl—S(O)— —phenyl— —3-NH—SO₂— phenyl 397 n-propyl absent —phenyl——3-NH—SO₂— phenyl 497 n-propyl —S— —phenyl— —3-NH—SO₂— 2,4,6- trimethyl-phenyl

Representative compounds of formula (II) are as listed in Tables 9-13,below. TABLE 9 Compounds of Formula (II)

ID No.

Q³ R² R³ 72 —(S)-cyclopentyl- —2-(R)-C(O)—N(CH₃) cyclohexyl phenyl 77—(S)-cyclopentyl- —3-(R)-C(O)—N(CH₃)— cyclohexyl phenyl 81—(R)-cyclohexyl- —2-(S)-C(O)—N(CH₃)— cyclohexyl phenyl 87—(S)-cyclohexyl- —2-(R)-C(O)—N(CH₃)— cyclohexyl phenyl 93-3-pyrrolidinyl- —1-C(O)O— t-butyl phenyl 94 —phenyl— —3-C(O)—N(CH₃)—cyclohexyl phenyl 118 -9-fluorenyl- —2-C(O)—N(CH₃)— cyclohexyl phenyl119 -3-pyrrolidinyl- —1-C(O)— cyclohexyl phenyl 120 -3-pyrrolidinyl-—1-C(O)— cyclopentyl phenyl 124 -9-fluorenyl- —1-C(O)-N(cyclohexyl)—cyclohexyl phenyl 125 -9-fluorenyl- —4-C(O)—N(CH₃)— cyclohexyl phenyl145 -1-indanyl- —6-C(O)—N(CH₃)— cyclohexyl phenyl 146 -1-(5-methoxy-—3-CH₂—C(O)—N(CH₃)— cyclohexyl phenyl indanyl)- 147 -9-fluorenyl-—4-C(O)-N(cyclohexyl)— cyclohexyl phenyl 353 -4-piperidinyl- —1-C(O)O—ethyl (3-(2-methoxy-4- methyl-phenyl)- sulfonyl-amino)- phenyl 362-4-piperidinyl- —1-C(O)O— ethyl 3-(2,4,6-trimethyl- phenyl-sulfonylamino)- phenyl 376 -4-piperidinyl- —1-C(O)O— ethyl3-(phenyl-sulfonyl- amino-phenyl) 499 -4-piperidinyl- —1-C(O)O— t-butylphenyl 510 -3-azepinyl- —1-C(O)O— t-butyl phenyl 522 -4-piperidinyl-—1-C(O)— cyclohexyl phenyl 523 -4-piperidinyl- —1-C(O)— 4-n-heptylphenyl 524 -4-piperidinyl- —1-C(O)— 1-adamantyl phenyl 550 -3-azepinyl-—1-C(O)— 1-adamantyl phenyl 551 -3-azepinyl- —1-C(O)— cyclohexyl phenyl552 -3-azepinyl- —1-C(O)— 4-n-heptyl phenyl 611 -3-piperidinyl- —1-C(O)—cyclohexyl phenyl 612 -3-piperidinyl- —1-C(O)— 4-n-heptyl phenyl 613-3-piperidinyl- —1-C(O)— isopentyl phenyl

TABLE 10 Compounds of Formula (II)

ID No (A²)_(c)

Q³ R² R³ 62 —methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl phenyl 89—methyl— -4-pyridyl- —2-C(O)—N(CH₃)— cyclohexyl phenyl 97 —methyl——phenyl— —4-C(O)—N(CH₃)— cyclohexyl phenyl 98 —methyl— —phenyl——3-C(O)—N(cyclohexyl)— cyclohexyl phenyl 100 —methyl— -trans-—4-C(O)—N(CH₃)— cyclohexyl phenyl cyclohexyl- 110 —methyl— —phenyl——3-C(O)—N(CH₃)— cyclohexyl 3-(phenyl- sulfonyl- amino)-phenyl 132—CH(phenyl)— —phenyl— —3-C(O)—N(cyclohexyl)— cyclohexyl phenyl 136—CH(phenyl)— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl phenyl 187 —methyl——phenyl— —3-C(O)—N(4-methyl- 4-methyl- phenyl cyclohexyl)— cyclohexyl188 —methyl— —phenyl— —3-C(O)—NH— 4-(amino- phenyl sulfonyl)-phenyl-ethyl— 192 —methyl— —phenyl— —3-C(O)—N(isopropyl)— cyclohexylphenyl 193 —methyl— —phenyl— —3-C(O)— 2-deca- phenyl hydro-iso-quinolinyl 197 —methyl— —phenyl— —3-C(O)—N(n- cyclopropyl- phenylpropyl)— methyl— 198 —methyl— —phenyl— —3-C(O)—N(2-ethyl-n- 2-ethyl-n-phenyl hexyl)— hexyl 204 —1-ethyl-methyl— —phenyl— —3-C(O)—N(CH₃)—cyclohexyl phenyl 209 —methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl3-methyl-phenyl 211 —methyl— —phenyl— —3-C(O)—N(isobutyl)— isobutylphenyl 212 —methyl— —phenyl— —3-C(O)— 1-deca- phenyl hydro- quinolinyl213 —methyl— —phenyl— —3-C(O)—NH— 4-methyl- phenyl cyclohexyl 222—methyl— —phenyl— —3-C(O)—NH— 2-(1-methyl- phenyl pyrrolidinyl)- ethyl—223 —methyl— —phenyl— —3-C(O)—N(CH₃)— 4-(1-methyl- phenyl piperidinyl)224 —methyl— —phenyl— —3-NH—C(O)O— t-butyl phenyl 228 —methyl— —phenyl——3-C(O)—N(CH₃)— cyclohexyl 3,5-dimethyl- phenyl 229 —methyl— —phenyl——3-C(O)—N(CH₃)— cyclohexyl 3-(methyl- carbonyl- amino)-phenyl 230—methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl 3-pyridyl 231 —methyl——phenyl— —3-C(O)—N(CH₃)— cyclohexyl 3-biphenyl 232 —methyl— —phenyl——3-C(O)—N(CH₃)— cyclohexyl 2-methoxy- phenyl 233 —methyl— —phenyl——3-C(O)—N(CH₃)— cyclohexyl 2-(5,6,7,8- tetrahydro- naphthyl) 234—methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-biphenyl 235 —methyl——phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-(amino- carbonyl- methyl)—phenyl236 —methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl 3-(phenyloxy)- phenyl286 —methyl —phenyl— —3-NH—C(O)— cyclohexyl phenyl 290 —methyl— —phenyl——3-NH—C(O)— t-butyl phenyl 292 —methyl— —phenyl— —3-C(O)—N(CH₃)—cyclohexyl 3-methoxy- phenyl 293 —methyl— —phenyl— —3-C(O)—N(CH₃)—cyclohexyl 2-methyl—phenyl 306 —methyl— —phenyl-3- —NH—C(O)— cyclohexylphenyl CH₂— 307 —methyl— —phenyl-3- —NH—C(O)— trifluoro- phenyl CH₂—methyl 310 —CH(cyclo-hexyl-methyl)— —phenyl— —C(O)—N(CH₃)— cyclohexylphenyl 315 —methyl— —phenyl-3- —NH—C(O)O— t-butyl phenyl CH₂— 316—1-phenyl-methyl— —phenyl— —3-C(O)—N(CH₃)— 4-(1-methyl- phenylpiperidinyl) 336 —methyl— —phenyl-3- —NH—C(O)— 1-adamantyl phenyl CH₂—337 —methyl— —phenyl-3- —NH—C(O)— benzhydryl phenyl CH₂— 338 —methyl——phenyl-3- —NH—C(O)— 4-n-heptyl phenyl CH₂— 339 —methyl— —phenyl-3-—NH—C(O)— 3-n-heptyl phenyl CH₂— 384 —methyl— -4-piperidinyl- —1-C(O)O—t-butyl 3-(phenyl- sulfonyl- amino)-phenyl 396 —methyl— —phenyl——3-C(O)O— methyl 3-(phenyl- sulfonyl- amino)-phenyl 419 —1-ethyl-methyl——phenyl— —3-C(O)—N(cyclohexyl)— cyclohexyl phenyl 424 —methyl— -2-furyl-—5-C(O)—N(CH₃)— cyclohexyl phenyl 443 —methyl— —phenyl— —3-C(O)—1-piperidinyl phenyl 451 —methyl— —phenyl— —3-C(O)—NH— cyclohexyl phenyl463 —methyl— —phenyl— —2-C(O)—N(CH₃)— cyclohexyl phenyl 467 —methyl——phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-methoxy-5- methyl—phenyl 468—methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-methoxy-6- methyl—phenyl469 —methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-(2-benz-thiazolyl)-5- methoxy- phenyl 470 —methyl— —phenyl— —3-C(O)—N(CH₃)—cyclohexyl 2-(2-benzo- thiazolyl)- phenyl 471 —methyl— —phenyl——3-C(O)—N(CH₃)— cyclohexyl 2-(1-pyrrolyl)- phenyl 472 —methyl— —phenyl——3-C(O)—N(CH₃)— cyclohexyl 2-(methyl- sulfonyl)- phenyl 473 —methyl——phenyl— —3-C(O)—N(CH₃)— cyclohexyl 3-(2- quinolinyl)- phenyl 474—methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-methylthio- phenyl 475—methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2,6-dimethyl- phenyl 477—methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2,6- dimethoxy- phenyl 478—methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-isopropoxy- phenyl 479—methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl 3-(dimethyl- amino)-phenyl480 —methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-allyl-6-methyl—phenyl 481 —methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl2-allyl-6- methoxy- phenyl 482 —methyl— —phenyl— —3-C(O)—N(CH₃)—cyclohexyl 2-methyl-6-n- propyl-phenyl 483 —methyl— —phenyl——3-C(O)—N(CH₃)— cyclohexyl 2-(1- pyrrolidinyl- carbonyl)- phenyl 503—methyl— -2-thienyl- —5-C(O)—N(CH₃)— cyclohexyl phenyl 508 —methyl—-2-pyridyl- —4-C(O)—N(CH₃)— cyclohexyl phenyl 509 —methyl— -4- —1-C(O)O—t-butyl phenyl piperidinyl- 512 —methyl— —phenyl— —3-C(O)—N(CH₃)—cyclohexyl 2-cyclopentyl- phenyl 513 —methyl— —phenyl— —3-C(O)—N(CH₃)—cyclohexyl 2-biphenyl- methyl— 514 —methyl— —phenyl— —3-C(O)—N(CH₃)—cyclohexyl 3-methoxy- benzyl 516 —methyl— —phenyl— —3-C(O)—N(CH₃)—cyclohexyl n-pentyl 517 —methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexylisopentyl 518 —methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl isobutyl 519—methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl isopropyl 520 —methyl——phenyl— —3-C(O)—N(CH₃)— cyclohexyl cyclopentyl 521 —methyl— —phenyl——3-C(O)—N(CH₃)— cyclohexyl cyclopentyl- methyl— 525 —methyl— -4-—1-C(O)— cyclohexyl phenyl piperidinyl- 526 —methyl— -4- —1-C(O)—4-n-heptyl phenyl piperidinyl- 527 —methyl— -4- —1-C(O)— 1-adamantylphenyl piperidinyl- 534 -1-cyclohexyl- —phenyl— —3-C(O)—N(CH₃)—cyclohexyl phenyl methyl— 559 -1-benzyl- -5-oxazolyl- —4-C(O)—N(CH₃)—cyclohexyl phenyl methyl— 606 -1-benzyl- -5-oxazolyl- —4-C(O)—NH—cyclohexyl phenyl methyl— 640 —methyl— -5-oxazolyl- —4-C(O)—NH—cyclohexyl phenyl 641 —methyl— -5-oxazolyl- —4-C(O)—N(CH₃)— cyclohexylphenyl

TABLE 11 Compounds of formula (II)

ID No (L¹)_(b) R³ 266 —CH═CH— phenyl 332 —CH(CH₃)— phenyl 404 —S—2-methyl-phenyl 405 —S— 3-methyl-phenyl 406 —S— 2-ethyl-phenyl 407 —S—4-isopropyl-phenyl 408 —S— 3,4-dimethyl-phenyl 409 —S—3,5-dimethyl-phenyl 410 —S— 4-methoxy-phenyl 411 —S—3,4-dimethoxy-phenyl 412 —S— 2-methoxy-phenyl 413 —S—4-methylthio-phenyl 414 —S— 1-naphthyl 415 —S— 2-naphthyl 416 —S—2-(methylaminocarbonyl)-phenyl 417 —S— 4-(methylcarbonylamino)-phenyl432 —NH— phenyl 433 —NH— 3-methoxy-phenyl 434 —NH— 4-methoxy-phenyl 435—NH— 3-methyl-phenyl 436 —NH— 2-naphthyl 437 —NH— 4-cyclohexyl-phenyl438 —NH— 4-(dimethylamino)-phenyl 439 —NH— 4-(4-morpholinyl)-phenyl 440—NH— 3-ethoxy-phenyl 441 —NH— 3,4-methylenedioxy-phenyl 442 —NH—4-methylthio-phenyl 476 —S— phenyl 549 —SO— phenyl 735 —SO₂— phenyl

TABLE 12 Compounds of formula (II)

ID No (A²)_(c)

Q³ R² R³ 138 —methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl phenyl 158—methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-(t-butyl-amino-sulfonyl)-phenyl 159 —methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl4-(3,5-dimethyl- isoxazolyl) 160 —methyl— —phenyl— —3-C(O)—N(CH₃)—cyclohexyl 2-(t-butyl-carbonyl- amino)-5-methoxy- phenyl 161 —methyl——phenyl— —3-C(O)—N(CH₃)— cyclohexyl 4-pyrazolyl 162 —methyl— —phenyl——3-C(O)—N(CH₃)— cyclohexyl 4-(amino-carbonyl)- phenyl 163 —methyl——phenyl— —3-C(O)—N(CH₃)— cyclohexyl 3-carboxy-phenyl 164 —methyl——phenyl— —3-C(O)—N(CH₃)— cyclohexyl 3-thienyl 165 —methyl— —phenyl——3-C(O)—N(CH₃)— cyclohexyl 3-methoxy-phenyl 166 —methyl— —phenyl——3-C(O)—N(CH₃)— cyclohexyl 3-(methyl-carbonyl- amino)-phenyl 167—methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-methoxy-phenyl 168—methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl 4-pyridyl 169 —methyl——phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-hydroxy-phenyl 170 —methyl——phenyl— —3-C(O)—N(CH₃)— cyclohexyl 3-pyridyl 171 —methyl— —phenyl——3-C(O)—N(CH₃)— cyclohexyl 3-biphenyl 172 —methyl— —phenyl——3-C(O)—N(CH₃)— cyclohexyl 2-(dimethylamino- methyl)-phenyl 173 —methyl——phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-(amino-carbonyl)- phenyl 174—methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-hydroxymethyl- phenyl 175—methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl 5-indolyl 176 —methyl——phenyl— —3-C(O)—N(CH₃)— cyclohexyl 3-methyl-phenyl 259 —methyl——phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2,6-dichloro-phenyl 260 —methyl——phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-chloro-phenyl 261 —methyl——phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-methyl-phenyl 262 —methyl——phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2,6-dimethyl-phenyl 263 —methyl——phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-cyano-phenyl 264 —methyl— —phenyl——3-C(O)—N(CH₃)— cyclohexyl 2,6-dimethoxy-phenyl 265 —methyl— —phenyl——3-C(O)—N(CH₃)— cyclohexyl 3-benzothienyl 267 —methyl— —phenyl——3-C(O)—N(CH₃)— cyclohexyl 4-cyclohexyl-phenyl 268 —methyl— —phenyl——3-C(O)—N(CH₃)— cyclohexyl 2-trifluoro-methyl-phenyl 320 —methyl——phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-ethyl-phenyl— 321 —methyl——phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-biphenyl 322 —methyl— —phenyl——3-C(O)—N(CH₃)— cyclohexyl 2-methylthio-phenyl 323 —methyl— —phenyl——3-C(O)—N(CH₃)— cyclohexyl 2-(methyl-carbonyl)- phenyl 324 —methyl——phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-trifluoro-methoxy- phenyl 325—methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-cyanomethyl- phenyl 326—methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-(phenyloxy)-phenyl 327—methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-benzyloxy-phenyl 328—methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl 2-(methyl-carbonyl-amino)-phenyl 329 —methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl2-ethoxy-phenyl 330 —methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl1-naphthyl 331 —methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl2-bromo-phenyl 333 —methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl2-nitro-phenyl 334 —methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl2-fluoro-phenyl 395 —1-ethyl-methyl— —phenyl— —3-C(O)—N(CH₃)— cyclohexyl2-methoxy-phenyl 396 —methyl— —phenyl— —3-C(O)O— methyl3-(phenyl-sulfonyl- amino)-phenyl 418 —1-ethyl-methyl— —phenyl——3-C(O)—N(cyclo- cyclohexyl 2-methoxy-phenyl hexyl)—

TABLE 13 Compounds of Formula (II)

ID No R¹ Q³ R² R³ 605 methoxy —3-C(O)—N(CH₃)— cyclohexyl 2-methoxy-phenyl 607 methyl- —3-C(O)—N(CH₃)— cyclohexyl 2-methoxy- carbonyl phenyl

Table 14 below lists representative intermediates and by-products in thepreparation of the compounds of formula (I), formula (II) and/or formula(III) of the present invention. TABLE 14 Intermediates or By-Products

The present invention is further directed to compounds of formula (CI),compounds of formula (CII) and compounds of formula (CIII)

wherein R⁰, R¹, R², R³, R⁶, R⁷, R⁸, R¹⁰, L¹, L², L³, a, b, c, d, A¹, A²,Q¹, Q³and

are as herein defined. The compounds of formula (CI), (CII) and (CIII)are useful as intermediates in the preparation of the compounds offormula (I), (II) and/or (III) of the present invention.

As used herein, unless otherwise noted, the term “halogen” shall meanchlorine, bromine, fluorine and iodine.

As used herein, unless otherwise noted, the term “alkyl” whether usedalone or as part of a substituent group, includes straight and branchedchains. For example, alkyl radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl,hexyl, heptyl, octyl, nonyl, decyl, and the like. Similarly, the term“C₁₋₈alkyl” shall include straight and branched chains comprising one toeight carbon atoms. The term “alkyl” may also encompass multivalentradicals where indicated in the specification and claims (e.g. A¹ and A²are described as C₁₋₄alkyl groups, as shown in the formulas and would beunderstood by those of ordinary skill the art to be divalent linkinggroups that may be further substituted, for example —CH₂—, —CH₂CH₂—,—CH₂—CH(CH₃)—, and the like).

As used herein, unless otherwise noted, “alkoxy” shall denote an oxygenether radical of the above described straight or branched chain alkylgroups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy,n-hexyloxy and the like.

As used herein, unless otherwise noted, the terms “halogen substitutedC₁₋₄alkyl” and “halogenated C₁₋₄alkyl”, shall mean a straight orbranched chain alkyl group comprising one to four carbon atoms, whereinthe alkyl is substituted with one or more, preferably one to five, morepreferably one to three halogen atoms. Preferably, the halogen isselected from the group consisting of chloro and fluoro.

Similarly, the terms “halogen substituted C₁₋₄alkoxy” and “halogenatedC₁₋₄alkoxy” shall mean a straight or branched chain alkoxy groupcomprising one to four carbon atoms, wherein the alkoxy is substitutedwith one or more, preferably one to five, more preferably one to threehalogen atoms. Preferably, the halogen is selected from the groupconsisting of chloro and fluoro.

As used herein, unless otherwise noted, the term “hydroxy substitutedC₁₋₄alkyl” shall mean a straight or branched chain C₁₋₄alkyl, whereinthe C₁₋₄alkyl is substituted with one or more, preferably one to threehydroxy groups, more preferably one to two hydroxy groups. Mostpreferably, the C₁₋₄alkyl group is substituted with one hydroxy group.Preferably, wherein the C₁₋₄alkyl group has a terminal carbon atom, thehydroxy group is bound at said terminal carbon atom.

As used herein, unless otherwise noted, the term “carboxy substitutedC₁₋₄alkyl” shall mean a straight or branched chain C₁₋₄alkyl, whereinthe C₁₋₄alkyl is substituted with one or more, preferably one to threecarboxy groups, more preferably one to two carboxy groups. Mostpreferably, the C₁₋₄alkyl group is substituted with one carboxy group.Preferably, wherein the C₁₋₄alkyl group has a terminal carbon atom, thecarboxy group is bound at said terminal carbon atom.

As used herein, unless otherwise noted, “aryl” shall refer to fullyconjugated aromatic ring structures such as phenyl, naphthyl, and thelike.

As used herein, unless otherwise noted, “C₁₋₄aralkyl” shall mean anyC₁₋₄alkyl group substituted with an aryl group such as phenyl, naphthyland the like. For example, benzyl, phenylethyl, phenylpropyl,naphthylmethyl, and the like. Unless otherwise noted, the “C₁₋₄aralkyl”group is bound through the alkyl portion. For example, phenylethyl—isbound through the terminal carbon atom of the ethyl group (i.e.phenyl-CH₂—CH₂—).

As used herein, unless otherwise noted, the term “cycloalkyl” shall meanany stable monocyclic, bicyclic, polycyclic, bridged or spiro-bound,saturated ring system. Suitable examples include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, norboranyl, adamantyl, spiropentane, 2,2,2-bicyclooctyl, andthe like. Unless otherwise noted, “cycloalkyl” groups do not contain N,O or S heteroatoms.

As used herein, unless otherwise noted, the term “partially unsaturatedcarbocyclyl” shall mean any stable monocyclic, bicyclic, polycyclic,bridge or spiro-bound ring system containing at least one carbon atomwhich is not part of an unsaturated bond (i.e. a double or triple bond)or any bicyclic, polycyclic, bridged or spiro-bound, partially aromatic(e.g. benzo-fused) rings system. Suitable examples include, but are notlimited to 1,2,3,4-tetrahydro-naphthyl, fluorenyl,9,10-dihydroanthracenyl, indanyl, and the like. Unless otherwise noted,“partially unsaturated carbocyclyl” groups do not contain N, O or Sheteroatoms.

As used herein, unless otherwise noted, “heteroaryl” shall denote anyfive or six membered monocyclic aromatic ring structure containing atleast one heteroatom selected from the group consisting of O, N and S,optionally containing one to three additional heteroatoms independentlyselected from the group consisting of O, N and S; or a nine or tenmembered bicyclic aromatic ring structure containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heteroaryl group may beattached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to,pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl,isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl,benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, tetrazolyl, triazolyl, and the like.Preferred heteroaryl groups include furyl, thienyl, imidazolyl, pyridyl,triazolyl, benzimidazolyl and tetrazolyl.

As used herein, the term “heterocycloalkyl” shall denote any five toseven membered monocyclic, saturated or partially unsaturated ringstructure containing at least one heteroatom selected from the groupconsisting of O, N and S, optionally containing one to three additionalheteroatoms independently selected from the group consisting of O, N andS; or a nine to ten membered saturated, partially unsaturated orpartially aromatic (e.g. benzo-fused) bicyclic ring system containing atleast one heteroatom selected from the group consisting of O, N and S,optionally containing one to four additional heteroatoms independentlyselected from the group consisting of O, N and S. The heterocycloalkylgroup may be attached at any heteroatom or carbon atom of the ring suchthat the result is a stable structure.

Examples of suitable heterocycloalkyl groups include, but are notlimited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl,imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl,morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,indolinyl, chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl,tetrahydropyranyl, azepinyl, 2,3-dihydro-1,4-benzodioxanyl, and thelike. Preferred heterocycloalkyl groups include piperidinyl,morpholinyl, tetrahydropyranyl (preferably tetrahydropyran-2-yl ortetrahydropyran-6-yl) and azepinyl.

As used herein, unless otherwise noted, the term “spiro-heterocyclyl”shall mean any spiro-bound ring structure wherein the spiro-bound ringstructure contains at least one heteroartom selected from O, S or N.Suitable examples include, but are not limited to1,4-dioxaspiro[4.5]decyl, 1-oxa-4-azaspiro[4.5]decyl,1-thia-4azaspiro[4.5]decyl, 1,4-diazaspiro[4.5]decyl,1,3-diazaspiro[4.5]dec-2-2nyl and 1-oxa-azaspiro[4.5]dec-2-enyl.Preferred spiro-heterocyclyl groups include

As used herein, the notation “*” shall denote the presence of astereogenic center.

When a particular group is “substituted” (e.g., cycloalkyl, aryl,heterocycloalkyl, heteroaryl, etc.), that group may have one or moresubstituents, preferably from one to five substituents, more preferablyfrom one to three substituents, most preferably from one to twosubstituents, independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

As used herein, unless otherwise noted, the term “aprotic solvent” shallmean any solvent that does not yield a proton. Suitable examplesinclude, but are not limited to DMF, dioxane, THF, acetonitrile,pyridine, dichloroethane, dichloromethane, MTBE, toluene, and the like.

As used herein, unless otherwise noted, the term “leaving group” shallmean a charged or uncharged atom or group which departs during asubstitution or displacement reaction. Suitable examples include, butare not limited to, Br, Cl, I, mesylate, tosylate, and the like.

As used herein, unless otherwise noted, the term “nitrogen protectinggroup” shall mean a group which may be attached to a nitrogen atom toprotect said nitrogen atom from participating in a reaction and whichmay be readily removed following the reaction. Suitable nitrogenprotecting groups include, but are not limited to carbamates—groups ofthe formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl,benzyl, phenylethyl, CH₂═CH—CH₂—, and the like; amides—groups of theformula —C(O)—R′ wherein R′ is for example methyl, phenyl,trifluoromethyl, and the like; N-sulfonyl derivatives—groups of theformula —SO₂—R″ wherein R″ is for example tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogenprotecting groups may be found in texts such as T. W. Greene & P. G. M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999.

As used herein, unless otherwise noted, the term “oxygen protectinggroup” shall mean a group which may be attached to an oxygen atom toprotect said oxygen atom from participating in a reaction and which maybe readily removed following the reaction. Suitable examples include,but are not limited to methyl, benzyl, trimethylsilyl,tert-butyldimethylsilyl, acetate, 1-ethoxyethyl, and the like. Othersuitable nitrogen protecting groups may be found in texts such as T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenyl-(C₁-C₆alkyl)-aminocarbonyl-(C₁-C₆alkyl)-”substituent refers to a group of the formula

Unless otherwise noted, the position at which substituent groups on thecompounds of formula (I), formula (II) and formula (III) are bound tothe 2-amino-quinazoline core shall be denoted as follows:

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows:

-   Ac=Acetyl (i.e. —C(O)—CH₃)-   ACN=Acetonitrile-   AD=Alzheimer's Disease-   AgOAc=Silver Acetate-   BACE=β-secretase-   BH(OAc)₃=Triacetoxy Borohydride-   BOC or Boc=t-Butoxycarbonyl-   (Boc)₂O=Boc Anhydride-   Cbz=Carbobenzyloxy-   DBU=1,8-iazabicyclo[5.4.0]undec-7-ene-   DCC=N,N′-Dicyclohexylcarbodiimide-   DCE=1,2-Dichloroethane-   DCM=Dichloromethane-   DEA=diethylamine-   DEAD=Diethylazodicarboxylate-   DIAD=Diisopropylazodicarboxylate-   DIPE=Diisopropyl Ether-   DIPCDI=1,3-Diisopropylcarbodiimide-   DIPEA or DIEA=Diisopropylethylamine-   DMA=N,N-Dimethylacetamide-   DMAP=4-N,N-Dimethylaminopyridine-   DME=Dimethoxyethane-   DMF=N,N-Dimethylformamide-   DMSO=Dimethylsulfoxide-   dppf=1,1′-Bis(diphenylphosphino)ferrocene-   EDC=1-(3-Dimethylaminoproyl)-3-ethylcarbodiimide-hydrochoride-   EDCl=1-(3-Dimethylaminopropyl)3-ethylcarbodiimide hydrochloride-   Et=Ethyl (—CH₂CH₃)-   Et₃N=Triethylamine-   Et₂O=Diethyl Ether-   EtOAc=Ethyl acetate-   EtOH=Ethanol-   HOAc=Acetic acid-   HATU=O-(7-Azabenzotriazol-1-yl)-N,N,N″,N″-Tetramethyl Uronium    Hexafluorophosphate-   HBTU=O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HEPES=4-(2-Hydroxyethyl)-1-Piperizine Ethane Sulfonic Acid-   HOBT or HOBt=1-Hydroxybenzotriazole-   HPLC=High Pressure Liquid Chromatography-   LAH=Lithium Aluminum Hydride-   μwave=Microwave-   MCPBA=2-(4-Chloro-2-methylphenoxy)acetic acid-   Me=Methyl-   MeCN=Acetonitrile-   MeOH=Methanol-   MeONH₂ HCl=O-methylhydroxylamine hydrochloride-   MTBE=Methyl-tert-Butyl Ether-   Na(OAc)₃BH=Sodium triacetoxyborohydride-   NH₄OAc=Ammonium Acetate-   NMR=Nuclear Magnetic Resonance-   OXONE®=Potassium Monopersulfaphate Triple Salt-   Pd-C or Pd/C=Palladium on Carbon Catalyst-   Pt-C or Pt/C=Platinum on Carbon Catalyst-   Pd₂(OAc)₂=Palladium(II)acetate-   Pd₂(dba)₃=Tris(dibenzylidene acetone)dipalladium(0)-   Pd(dppf)Cl₂=Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium-   Pd(PPh₃)₄=tetrakistriphenylphosphine palladium (0)-   Pd(PCy₃)₂Cl₂=Dichlorobis(tricyclohexylphosphine)palladium-   PTSA or p-TsOH=p-Toluenesulfonic acid Monohydride-   q.s.=Quantum Sufficiat (Quantity Sufficient)-   RP-HPLC=Reverse Phase High Pressure Liquid Chromatography-   RT or rt=Room temperature-   SPE=Solid phase extraction-   t-BOC or Boc=Tert-Butoxycarbonyl-   TDA-1=Tris(3,6-Dioxaheptyl)amine-   TEA=Triethylamine-   TEMPO=2,2,6,6-Tetramethyl-1-piperidinyloxy Free Radical-   TFA=Trifluoroacetic Acid-   THF=Tetrahydrofuran-   TLC=Thin Layer Chromatography

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who is or has been the object oftreatment, observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Preferably, wherein a compound of the present invention is present anenantiomer, the enantiomer is present at an enantiomeric excess ofgreater than or equal to about 80%, more preferably, at an enantiomericexcess of greater than or equal to about 90%, more preferably still, atan enantiomeric excess of greater than or equal to about 95%, morepreferably still, at an enantiomeric excess of greater than or equal toabout 98%, most preferably, at an enantiomeric excess of greater than orequal to about 99%. Similarly, wherein a compound of the presentinvention is a diastereomer, the diastereomer is present at andiastereomeric excess of greater than or equal to about 80%, morepreferably, at an diastereomeric excess of greater than or equal toabout 90%, more preferably still, at an diastereomeric excess of greaterthan or equal to about 95%, more preferably still, at an diastereomericexcess of greater than or equal to about 98%, most preferably, at andiastereomeric excess of greater than or equal to about 99%.

Some of the crystalline forms for the compounds may exist as polymorphsand as such are intended to be included in the present invention. Inaddition, some of the compounds may form solvates with water (i.e.,hydrates) or common organic solvents, and such solvates are alsointended to be encompassed within the scope of this invention.

One skilled in the art will recognize that wherein a reaction step ofthe present invention may be carried out in a variety of solvents orsolvent systems, said reaction step may also be carried out in a mixtureof the suitable solvents or solvent systems.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography or recrystallization. The compounds may be prepared inracemic form, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution. The compounds may, forexample, be resolved into their component enantiomers by standardtechniques, such as the formation of diastereomeric pairs by saltformation with an optically active acid, such as(−)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acidfollowed by fractional crystallization and regeneration of the freebase. The compounds may also be resolved by formation of diastereomericesters or amides, followed by chromatographic separation and removal ofthe chiral auxiliary. Alternatively, the compounds may be resolved usinga chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1999. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts includethe following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methyinitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

Representative acids and bases which may be used in the preparation ofpharmaceutically acceptable salts include the following: acids includingacetic acid, 2,2-dichloroactic acid, acylated amino acids, adipic acid,alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid,benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid,camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid,caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid,dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronicacid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hipuric acid,hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lacticacid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid,(±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotincacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitric acid,pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid,4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid,sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid,p-toluenesulfonic acid and undecylenic acid; and

bases including ammonia, L-arginine, benethamine, benzathine, calciumhydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

The present invention further comprises pharmaceutical compositionscontaining one or more compounds of formula (I) and/or formula (II)and/or formula (III) with a pharmaceutically acceptable carrier.Pharmaceutical compositions containing one or more of the compounds ofthe invention described herein as the active ingredient can be preparedby intimately mixing the compound or compounds with a pharmaceuticalcarrier according to conventional pharmaceutical compounding techniques.The carrier may take a wide variety of forms depending upon the desiredroute of administration (e.g., oral, parenteral). Thus for liquid oralpreparations such as suspensions, elixirs and solutions, suitablecarriers and additives include water, glycols., oils, alcohols,flavoring agents, preservatives, stabilizers, coloring agents and thelike; for solid oral preparations, such as powders, capsules andtablets, suitable carriers and additives include starches, sugars,diluents,.granulating agents, lubricants, binders, disintegrating agentsand the like. Solid oral preparations may also be coated with substancessuch as sugars or be enteric-coated so as to modulate major site ofabsorption. For parenteral administration, the carrier will usuallyconsist of sterile water and other ingredients may be added to increasesolubility or preservation. Injectable suspensions or solutions may alsobe prepared utilizing aqueous carriers along with appropriate additives.

To prepare the pharmaceutical compositions of this invention, one ormore compounds of the present invention as the active ingredient isintimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, through other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, of from about 0.1-1000 mg and maybe given at a dosage of from about 0.1-500 mg/kg/day. The dosages,however, may be varied depending upon the requirement of the patients,the severity of the condition being treated and the compound beingemployed. The use of either daily administration or post-periodic dosingmay be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the. active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 1000 mg,preferably, from about 0.1 to about 500 mg, of the active ingredient ofthe present invention. The tablets or pills of the novel composition canbe coated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of material can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating central nervous system disorders described in thepresent invention may also be carried out using a pharmaceuticalcomposition comprising any of the compounds as defined herein and apharmaceutically acceptable carrier. The pharmaceutical composition maycontain between about 0.1 mg and 1000 mg, preferably about 50 to 500 mg,of the compound, and may be constituted into any form suitable for themode of administration selected. Carriers include necessary and inertpharmaceutical excipients, including, but not limited to, binders,suspending agents, lubricants, flavorants, sweeteners, preservatives,dyes, and coatings. Compositions suitable for oral administrationinclude solid forms, such as pills, tablets, caplets, capsules (eachincluding immediate release, timed release and sustained releaseformulations), granules, and powders, and liquid forms, such assolutions, syrups, elixirs, emulsions, and suspensions. Forms useful forparenteral administration include sterile solutions, emulsions andsuspensions.

Advantageously, one or more of the compounds of the present inventionmay be administered in a single daily dose, or the total daily dosagemay be administered in divided doses of two, three or four times daily.Furthermore, compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal skin patches well known to those of ordinary skill in thatart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phophatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,pQlyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment of disorders of the central nervous system isrequired.

The daily dosage of the products may be varied over a wide range from0.01 to 1,000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250, 500 and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Aneffective amount of the drug is ordinarily supplied at a dosage level offrom about 0.01 mg/kg to about 1000 mg/kg of body weight per day.Preferably, the range is from about 0.5 to about 500 mg/kg of bodyweight per day, most preferably, from about 1.0 to about 250 mg/kg ofbody weight per day. The compounds may be administered on a regimen of 1to 4 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

Compounds of formula (I) may be prepared according to the generalprocess outlined in Scheme 1.

Accordingly, a suitably substituted compound of formula (X), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (XI), a known compound orcompound prepared by known methods, in the presence of a reducing agentsuch as NaBH(OAc)₃, and the like, in an organic solvent such asdichloromethane, 1,2-dichloroethane, THF, acetonitrile, and the like; orin the presence of a reducing agent such as NaBH₃CN, NaBH₄, and thelike, in an organic solvent such as methanol, acetonitrile, and thelike; to yield the corresponding compound of formula (XII).

The compound of formula (XII) is reacted with hydrogen gas, in thepresence of a catalyst such as Pd on carbon (Pd/C), and the like, in aprotic solvent such as methanol, ethanol, and the like, to yield thecorresponding compound of formula (XIII). Alternatively, the compound offormula (XII) is reacted with a reducing agent such as stannouschloride, and the like, in an organic solvent such as methanol, ethanol,ethyl acetate, THF and the like, or in acid such as concentrated HCI,and the like; or with a reducing agent such as zinc, in the presence ofan acid source such as.ammonium chloride, calcium chloride, HBr, and thelike, in an organic solvent such as methanol, ethanol, ethyl acetate,and the like, or in a mixture of an organic solvent and water as aco-solvent, or in aqueous acid such as acetic acid, and the like, toyield the corresponding compound of formula (XIII).

The compound of formula (XIII) is reacted with cyanogen bromide, and thelike, in an organic solvent such as methanol, ethanol, toluene, and thelike, to yield the corresponding compound of formula (Ia).Alternatively, the compound of formula (XIII) is reacted with2-methyl-2-thiopseudourea, in the presence of an acid such ashydrochloric acid, sulfuric acid, and the like, in an organic solventssuch as butanol, and the like, to yield the corresponding compound offormula (Ia).

One skilled in.the art will recognize that compounds of formula (I)wherein the amine bound at the 2-position of the core structure issubstituted with methyl-carbonyl-may be prepared from the correspondingcompound of formula (Ia) above by reacting with a suitably substitutedanhydride or chloroformate, in the presence of a base such as TEA,DIPEA, pyridine, DMAP, and the like, in an organic solvent such as DCM,chloroform, THF, and the like.

One skilled in the art will further recognize that compounds of formula(I) wherein the amine bound at the 2-position of the core structure issubstituted with hydroxy or methoxy may be prepared from thecorresponding compound of formula (Ia) by reacting the compound offormula (XIII) with a reagent such as carbon disulfide,1,1′-thiocarbonyldiimidazole, thiophosgene, and the like, in thepresence of a base such as NaOH, KOH, DIPEA, and the like, in an organicsolvent such as methanol, ethanol, acetonitrile, DMF, and the like, orin a mixture of an organic solvent and water, to convert the 2-positionamine group on the compound of formula (XIII) to the correspondingthiourea. The thiourea is then reacted with a methylating agent such asmethyl iodide, dimethyl sulfide, and the like, in the presence of a basesuch as NaOH, NaH, DMAP, and the like, in an organic solvent such asDMF, acetone, THF, diethyl ether, and the like, to convert the thioureato the corresponding thiomethyl compound. The thiomethyl compound isthen reacted with N-hydroxylamine or N-methoxyamine, in the presence ofa base such as TEA, DIPEA, pyridine, and the like, in an organic solventsuch as DMF, acetonitrile, THF, methanol, and the like, optionally inthe presence of a thiophilic reagent such as HgCl₂, AgOAc, and the like,to yield the corresponding compound of formula (I) wherein R¹ is hydroxyor methoxy..

Compounds of formula (I) wherein R⁰ is methyl or trifluoromethyl may beprepared according to the process outlined in Scheme 1 above bysubstituting a suitably substituted compound of formula (XIV)

for the compound of formula (X).

Compounds of formula (I) wherein Q¹ is —NH—C(O)— may alternatively beprepared according to the process outlined in Scheme 2.

Accordingly, a suitably substituted compound of formula (XV), whereinPg¹ is a suitable nitrogen protecting group such as Cbz, BOC, and thelike, preferably BOC, a known compound or compound prepared by knownmethods, (for example by reacting the compound of formula (X), asdefined above, with a compound of the formula NH₂-A¹-NHPg¹ and thenreducing the nitro group to the corresponding amine), is reacted withcyanogen bromide, in an organic solvent such as methanol, ethanol,toluene, and the like, to yield the corresponding compound of formula(XVI). Alternatively, the compound of formula (XV) is reacted with2-methyl-2-thiopsuedourea, in the presence of an acid such ashydrochloric acid, sulfuric acid, and the like, in an organic solventsuch as ethanol, butanol, xylene, or dioxane, or in an-aqueous solventsuch as water to yield the corresponding compound of formula (XVI).

The compound of formula (XVI) is de-protected according to knownmethods, to yield the corresponding compound of formulae (XVII). Forexample, wherein Pg¹ is BOC, the compound of formula (XVI) isde-protected by reacting with an acid such as TFA, HCI, formic acid, andthe like; wherein Pg¹ is Cbz, the compound of formula (XVI) isde-protected by reacting with a hydrogen source such as H_(2(g)) in thepresence of a catalyst. (See for example, Protective Groups in OrganicChemistry, ed. J. F. W. McOmie, Plenum Press, 1973; or T. W. Greene & P.G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons,1999)

The compound of formula (XVII) is reacted with a suitably substitutedacid chloride, a compound of formula (XVIII), a known compound orcompound prepared by known methods, in the presence of a base such asTEA, DIPEA, pyridine, and the like, in an organic solvent such asdioxane, DCM, chloroform, and the like; to yield the correspondingcompound of formula (Ib).

One skilled in the art will recognize that compounds of formula (I)wherein Q is —NH—C(S)—NH— may be similarly prepared according to theprocess outlined in Scheme 2 above, by reacting the compound of formula(XVII) with a suitably substituted isothiocyanate, a compound of theformula R²—NCS, a known compound or compound prepared by known methods,in an organic solvent such as dioxane, dichloromethane, chloroform, andthe like.

One skilled in the art will further recognize that compounds of formula(I) wherein Q is —NH—C(O)—NH— may be similarly prepared according to theprocess outlined in Scheme 2 above, by reacting the compound of formula(XVII) with a suitably substituted isocyanate, a compound of the formulaR²—NCO, a known compound or compound prepared by known methods, in anorganic solvent such as dioxane, DCM, chloroform, and the like.

One skilled in the art will further recognize that compounds of formula(I) wherein Q is —NH—C(O)—O— may be similarly prepared according to theprocess outlined in Scheme 2 above, by reacting the compound of formula(XVII) with a suitably substituted chloroformate, a compound of theformula R²—O—C(O)—Cl, a known compound or compound prepared by knownmethods, in the presence of a base such as TEA, DIPEA, pyridine, and thelike, in an organic solvent such as dioxane, DCM, chloroform, and thelike.

One skilled in the art will further recognize that compounds of formula(I) wherein Q is —NH—SO₂— may be similarly prepared according to theprocess outlined in Scheme 2 above, by reacting the compound of formula(XVII) with a suitably substituted sulfonyl chloride, a compound of theformula R²—SO₂—Cl, a known compound or compound prepared by knownmethods, in the presence of a base such as TEA, DIPEA, pyridine, and thelike, in an organic solvent such as dioxane, DCM, chloroform, and thelike.

Compounds of formula (I) wherein Q¹ is —NH— and wherein R² is selectedfrom the group consisting of C₁₋₈alkyl, cycloalkyl-C₁₋₄alkyl-,C₁₋₄aralkyl, partially unsaturated carbocyclyl-C₁₋₄alkyl-,heteroaryl-C₁₋₄alkyl- and heterocycloalkyl-C₁₋₄alkyl- may alternativelybe prepared according to the process outlined in Scheme 3.

Accordingly, a suitably substituted compound of formula (XVII) isreacted with a suitably substituted aldehyde, a compound of formula(XIX), wherein R^(2a) is C₁₋₇alkyl, cycloalkyl-C₀₋₃alkyl-, C₀₋₃aralkyl,partially unsaturated carbocyclyl-C₀₋₃alkyl-, heteroaryl-C₀₋₃alkyl- orheterocycloalkyl-C₀₋₃alkyl-, a known compound or compound prepared byknown methods,. in the presence of a reducing agent such as NaBH(OAc)₃,and the like, in an aprotic solvent such as DCM, DCE, THF, and the like;or in the presence of a reducing agent such as NaCNBH₃, and the like, inan organic solvent such as methanol, ethanol, THF, acetonitrile, and thelike, to yield the corresponding compound of formula (Ic).

One skilled in the art will recognize that wherein R² is selected fromthe group consisting of —CH(C₁₋₄alkyl)-(C₁₋₄alkyl),cycloalkyl-CH(C₁₋₄alkyl)-, aryl-CH(C₁₋₄alkyl)-, partially unsaturatedcarbocyclyl-CH(C₁₋₃alkyl)-, heteroaryl-CH(C₁₋₄alkyl)- andheterocycloalkyl-CH(C₁₋₄alkyl)-, the compound of formula (I) may beprepared according to the process outlined in Scheme 4.

Accordingly, a suitably substituted compound of formula (XVII) isreacted with a suitably substituted ketone, a compound of formula (XX),wherein R^(2b) is selected from (C₁₋₃alkyl), cycloalkyl, aryl, partiallyunsaturated carbocyclyl, heteroaryl or heterocycloalkyl, a knowncompound or compound prepared by known methods, in the presence of areducing agent such as NaBH(OAc)₃, and the like, in an aprotic solventsuch as DCM, DCE, THF, and the like; or in the presence of a reducingagent such as NaCNBH₃, and the like, in an organic solvent such asmethanol, ethanol, THF, acetonitrile, and the like, to yield thecorresponding compound of formula (Id).

One skilled in the art will further recognize that compounds of formula(I) wherein Q¹ is NH and R² is selected from the group consisting ofcycloalkyl, partially unsaturated carbocyclyl and heterocycloalkyl maybe similarly prepared according to the process outlined in Scheme 4above, by substituting a suitably substituted ketone (i.e. a cycloalkylketone such as cyclohexone; a partially unsaturated carbocyclyl ketone;or a heterocycloalkyl ketone) for the compound of formula (XX).

Compounds of formula (II) may be prepared according to the processesdescribed above by selecting and substituting suitably substitutedreagents and intermediates for those disclosed within the schemes.

For example, compounds of formula (II) may be prepared according to theprocess outlined in Scheme 1 above, by selecting and substituting, asuitably substituted compound of formula (XXI)

a known compound or compound prepared by known methods, for the compoundof (XI).

Compounds of formula (III) wherein d is 1, may be prepared according tothe process outlined in Scheme 5.

Accordingly, a suitably substituted compound of formula (XXII), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (XXIII), a known compound orcompound prepared by known methods, wherein W is selected from -L³-R⁸ ora reactive group such as NH₂, CN, Br, OH and the like; in the presenceof a base such as K₂CO₃, Na₂CO₃, Cs₂CO₃, TEA, OIPEA, pyridine, and thelike, in a polar organic solvent such as DMF, DMA, and the like, at anelevated temperature in the range of from about 70° C. to about 150° C.,preferably at an elevated temperature in the range of about 80° C. toabout 100° C., to yield the corresponding compound of formula (XXIV).

One skilled in the art will recognize that in the process step describedabove, in the compound of formula (XXII), the Cl may be replaced with Fand reacted as decribed above, to yield the compound of formula (XXIV).

The compound of formula (XXIV) is reacted with a suitably substitutedcompound of formula (XXV), a known compound or compound prepared byknown methods, in an organic solvent such as DCE, DCM, THF, and thelike, in the presence of a reducing agent such as BH(OAc)₃, NaCNBH₃, andthe like, to yield the corresponding compound of formula (XXVI).

Alternatively, the compound of formula (XXII) (or the compound offormula (XXII) wherein the Cl is replaced with F) is protected,according to known methods, for example as an acetal of the formula(XXIX)

and then reacted with a suitably substituted compound of formula (XXIII)to yield the corresponding protected version of the compound of formula(XXIV), which is the de-protected and reacted with the compound offormula (XXV), to yield the corresponding compound of formula (XXVI).

The compound of formula (XXVI) is reacted with hydrogen gas, in thepresence of a catalyst such as Pd on carbon (Pd/C), and the like, in aprotic solvent such as methanol, ethanol, and the like, to yield thecorresponding compound of formula (XXVII). Alternatively, the compoundof formula (XXVI) is reacted with a reducing agent such as stannouschloride, and the like, in an organic solvent such as methanol, ethanol,ethyl acetate, THF and the like, or in acid such as concentrated HCl,and the like; or with a reducing agent such as zinc, in the presence ofan acid source such as ammonium chloride, calcium chloride, HBr, and thelike, in an organic solvent such as methanol, ethanol, ethyl acetate,and the like, or in a mixture of an organic solvent and water as aco-solvent, or in aqueous acid such as acetic acid, and the like, toyield the corresponding compound of formula (XXVII).

The compound of formula (XXVII) is reacted with cyanogen bromide, andthe like, in an organic solvent such as methanol, ethanol, toluene, andthe like, to yield the corresponding compound of formula (XXVIII).Alternatively, the compound of formula (XXVII) is reacted with2-methyl-2-thiopseudourea, in the presence of an acid such ashydrochloric acid, sulfuric acid, and the like, in an organic solventsuch as butanol, and the like, to yield the corresponding compound offormula (XXVIII).

One skilled in the art will recognize that wherein W is -L³-R², thecompound of formula (XXVIII) is the corresponding compound of formula(III).

Wherein the compound of formula (XXVIII), W is other than -L³-R², thecompound of formula (XXVIII) is further reacted with according to knownmethods to yield the corresponding compound of formula (III).

For example, wherein W is NH₂, the compound of formula (XXVIII) isreacted with a suitably substituted aldehyde or cyclic ketone, forexample an aldehyde, a compound of the formula R⁸—CHO or a cyclic ketonesuch as cyclohexanone, to yield the corresponding compound of formula(III) wherein L³ is —NH—.

Alternatively, wherein W is NH₂, the compound of formula (XXVIII) isreacted with a suitably substituted acid, a compound of the formulaR⁸—C(O)—OH, according to known methods, to yield the correspondingcompound of formula (III) wherein L³ is —NH—C(O)—.

Alternatively still, wherein W is NH₂, the compound of formula (XXVIII)is reacted with a suitably substituted sulfonyl chloride, a compound ofthe formula R⁸—SO₂—Cl, or a suitably substituted acid chloride, acompound of the formula R⁸—C(O)—Cl, according to known methods, to yieldthe corresponding compound of formula (III) wherein L³ is —NH—SO₂— or—NH—C(O)—, respectively.

Alternatively still, wherein W is CN, the cyano group on the compound offormula (XXVIII) is reduced according to known methods, to yield thecorresponding amine and then further functionalized according to knownmethods, for example, as described above.

Compounds of formula (III) wherein d is 1 may alternatively be preparedaccording to the process outlined in Scheme 6.

Accordingly, a suitably substituted compound of formula (XXIVa), acompound of formula (XXIV) wherein W is a reactive group such as CN,NH₂, Br, OH, and the like, is reacted according to known methods, toyield the corresponding compound of formula (XXX).

For example, wherein W is NH₂, the compound of formula (XXIVa) isreacted with a suitably substituted aldehyde or cyclic ketone, forexample an aldehyde, a compound of the formula R⁸—CHO or a cyclic ketonesuch as cyclohexanone, to yield the corresponding compound of formula(XXX) wherein L³is —NH—.

Alternatively, wherein W is NH₂, the compound of formula (XXIVa) isreacted with a suitably substituted acid, a compound of the formulaR⁸—C(O)—OH, according to known methods, to yield the correspondingcompound of formula (XXX) wherein L³ is —NH—C(O)—.

Alternatively still, wherein W is NH₂, the compound of formula (XXIVa)is reacted with a suitably substituted sulfonyl chloride, a compound ofthe formula R⁸—SO₂—Cl, or a suitably substituted acid chloride, acompound of the formula R⁸—C(O)—Cl, according to known methods, to yieldthe corresponding compound of formula (XXX) wherein L³ is —NH—SO₂— or—NH—C(O)—, respectively.

Alternatively still, wherein W is CN, the cyano group on the compound offormula (XXIVa) is reduced according to known methods, to yield thecorresponding amine and then further functionalized according to knownmethods, for example, as described above.

Alternatively still, wherein W is Br, the compound of formula (XXIVa) isreacted with a suitably substituted amine, a compound of the formulaR⁸—NH₂, or a compound of the formula R⁸—NH—R^(B), according to knownmethods, to yield the corresponding compound of formula (XXX) wherein L³is —NH—R⁸ or R⁸—(R^(B))N—, respectively.

Alternatively still, wherein W is OH, the compound of formula (XXIVa) isconverted to the corresponding triflate and then reacted with a suitablysubstituted amine, a compound of the formula R⁸—NH₂, or of a compound ofthe formula R⁸—NH—R^(B), to yield the corresponding compound of formula(XXX) wherein L³ is —NH—R⁸or R⁸—(R^(B))N—, respectively.

Wherein the compound of formula (XXIV), W is Br or OH, preferably thecompound of formula (XXIV) is reacted according to the process outlinedin Scheme 6.

The compound of formula (XXX) is then substituted for the compound offormula (XXIV) in the process outlined in Scheme 5 above, and reacted asdisclosed in Scheme 5 above, to yield the corresponding compound offormula (III).

Compounds of formula (III) wherein d is 0 may be prepared according tothe processes outlined in Schemes 5 and 6 above by substituting asuitably substituted compound of formula (XXXI)

for the compound of formula (XXIV), a known compound or compoundprepared by known methods. For example, the compound of formula (XXXI)may be prepared according to the process outlined in Scheme 7.

Accordingly, a suitably substituted compound of formula (XXXII), whereinT is selected from Cl, Br or I, a known compound or compound prepared byknown methods, is reacted with pinacol diborane (also known as4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]), a knowncompound, in the presence of a catalyst such as Pd(dppf)Cl₂, Pd₂(dba)₃,and the like, with a base such as potassium carbonate, potassiumacetate, and the like, in an organic solvent, such as DMSO, DME, and thelike, in the absence or presence of an aqueous co-solvent, such aswater, at an elevated temperature in the range of from about 50° C. toabout 130° C., preferably at an elevated temperature in the range offrom about 80° C. to. about 110° C., to yield the corresponding compoundof formula (XXXIII).

The compound of formula (XXXIII) is reacted with a suitably substitutedcompound of formula (XXXIV), wherein E is Br or I, and wherein W is-L³-R⁸ or a suitable reactive group such as NH₂, CN, Br, OH, and thelike, a known compound or compound prepared by known methods, (forexample as disclosed in Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,2457; Suzuki, A. J. Organomet. Chem. 1999, 576, 147), in the presence ofa catalyst such Pd(PPh₃)₄, Pd(dppf)Cl₂, and the like, in the presence ofa base such as Na₂CO₃, K₂CO₃, NaHCO₃, and the like, in a mixture of anorganic solvent such as toluene, DME, THF, MeOH, and the like, and aprotic solvent such as water, and the like, at an elevated temperaturein the range of from about 60° C. to about 150° C., preferably, at anelevated temperature in the range of from about 100° C. to about 120°C., optionally in the presence of microwave irradiation, to yield thecorresponding compound of formula (XXXI).

Compounds of formula (X) are known compounds or compounds which may beprepared according to known methods. Schemes 8-12 below outlineprocesses for the preparation of representative compounds of formula(X).

For example, compounds of formula (X) wherein (L¹)_(b) is —O— and R³ isfor example, aryl or heteroaryl, may be prepared according to any of theprocesses outlined in Scheme 8.

Accordingly, a suitably substituted compound of formula (XXXV), a knowncompound or compound prepared by known methods, wherein the phenyl ringmay be further optionally substituted with one to three R¹⁰ groups andwherein the F is bound at the carbon of the phenyl ring to which the-(L¹)_(b)-R³ group in the desired compound of formula (I) is to bebound;. is reacted with a suitably substituted compound of formula(XXXVI), a known compound or compound prepared by known methods, in thepresence of a base such as K₂CO₃, Cs₂CO₃, and the like, in an organicsolvent such as DMF, DMA, and the like, preferably DMF, at an elevatedtemperature in the range of from about 25° C. to about 150° C.,preferably, at an elevated temperature in the range of from about 100°C. to about 120° C., optionally in the presence of microwaveirradiation, to yield the corresponding compound of formula (XXXVII).

The compound of formula (XXXVII) is reacted. with an electrophilicformyl source such as DMF dimethyl acetal, DMF diethyl acetal, and thelike, in an organic solvent such as DMF, DMA, and the like, preferablyDMF; or with neat tripiperidinomethane, preferably under vacuum; or withneat tert-butoxy-bis(dimethyl)aminomethane, at an elevated temperaturein the range of from about 100° C. to about 150° C., preferably, at anelevated temperature in the range of from about 130° C. to about 140°C., followed by reaction with NaIO₄, and the like, in an organic solventsuch as THF, DME, and the like, in the presence of water as aco-solvent, to yield the corresponding compound of formula (Xa).

Alternatively, a suitably substituted compound of formula (XXXVIII)wherein J is F, a known compound or compound prepared by known methods,wherein the phenyl ring may be further optionally substituted with oneto three R¹⁰ groups and wherein the F is bound at the carbon of thephenyl ring to which the -(L¹)_(b)-R³ group in the desired compound offormula (I) is to be bound; is reacted with a suitably substitutedcompound of formula (XXXVI), a known compound or compound prepared byknown methods, in the presence of a base such as K₂CO₃, Cs₂CO₃, and thelike, in an organic solvent such as DMF, DMA, and the like, at anelevated temperature in the range of from about 100° C. to about 170°C., preferably, at an elevated temperature in the range of from about140° C. to about 160° C., to yield the corresponding compound of formula(Xa).

Alternatively, a suitably substituted compound of formula (XXXVIII)wherein J is OH, a known compound or compound prepared by known methods,wherein the phenyl ring may be further optionally substituted with oneto three R¹⁰ groups and wherein the OH is bound at the carbon of thephenyl ring to which the -(L¹)_(b)-R³ group in the desired compound offormula (I) is to be bound; is reacted with a suitably substitutedcompound of formula (XXXVI), under Mitsonobu conditions, for example, inthe presence of a phosphine reagent such as triphenylphosphine,tributylphosphine, and the like and in the presence of an acetylenedicarboxylate such as DEAD, DIAD, and the like, in an organic solventsuch as THF, DMF, and the like, to yield the corresponding compound offormula (Xa). Preferably, the Mitsonobu conditions are applied to thepreparation of compounds of formula (Xa) wherein R³ is C₁₋₄alkyl.

Alternatively still, a suitably substituted compound of formula(XXXVIII) wherein J is Cl or F, a known compound or compound prepared byknown methods, wherein the phenyl ring may be further optionallysubstituted with one to three Rlo groups and wherein the Cl or F isbound at the carbon of the phenyl ring to which the -(L¹)_(b)-R³ groupin the desired compound of formula (I) is to be bound; is reacted withCH(OCH₃)₃ in the presence of an acid catalyst such as p-TsOH, NH₄Cl,AlCl₃, and the like, in an organic solvent such as methanol, THF, andthe like, at an elevated temperature, preferably, at about refluxtemperature, to yield the corresponding compound of formula (XXXIX).

The compound of formula (XXXIX) is reacted with a suitably substitutedcompound of formula (XXVI), a known compound or compound prepared byknown methods, in the presence of a base such as K₂CO₃, Cs₂CO₃, and thelike, in an organic solvent such as DMF, DMA, and the like, at anelevated temperature in the range of from about 25° C. to about 150° C.,preferably, at an elevated temperature in the range of from about 100°C. to about 120° C., to yield the corresponding compound of formula(XXXX).

The compound of formula (XXXX) is hydrolyzed by reacting with an acidsuch as HCl, H₂SO₄, trifluoroacetic acid, and the like, in an organicsolvent such as THF, DCM, diethyl ether, and the like, in the presenceof water, to yield the corresponding compound of formula (Xa).

Compounds of formula (X) wherein (L¹)b is —S— may be similarly preparedaccording to the process described above by reacting a compound offormula (XXXVIII) wherein J is F, with a substituting a suitablysubstituted compound of the formula R³—SH (i.e. substituting thecompound of formula R³—SH for the compound of formula (XXXVI)). Theresulting compound may then be optionally, selectively oxidized to yieldthe corresponding compound of formula (X) wherein the —S— is oxidized to—SO— and/or —SO₂—.

Compounds of formula (X) wherein (L¹)_(b) is —NR^(N)—, may be similarlyprepared according to the process outlined in Scheme 7 above, byreacting a compound of formula (XXXVIII) wherein J is Br with a suitablysubstituted compound of the formula R³—NHR^(N), in the presence of acatalyst or mixture thereof, such as a 1:3 mixture of Pd₂(dba)₃ anddppf, and the like, in an organic solvent such as DMF, DME, toluene, andthe like; or a catalyst such as Pd₂(dba)₃ or Pd(dppf)Cl₂ in the presenceor a base such as Cs₂CO₃, NaOC(CH₃)₃, and the like, in an organicsolvent such as toluene, and the like, to yield the correspondingcompound of formula (X) wherein (L¹)_(b) is —NR^(N)—.

Compounds of formula (X) wherein (L¹)_(b) is —C(O)— may be preparedaccording to the processes disclosed in European Patent Number EP 0 371564 B1; Katritzky, A. R., Chassaing, C., Toader, D. and Gill, K., J.Chem. Research, (S), 1999, pp 504-505; Katritzky, A. R., Lang, H., Wang,Z., Zhang, Z. and Song, H., J. Org. Chem., 60,1990, pp 7619-7624; and/orVetelino, M. G. and Coe, J. W., Tetrahedron Lett., 35(2), 1994, pp219-22; with suitable modification, as would be clear to one of ordinaryskill in art.

Compounds of formula (X) wherein (L¹)_(b) is —C(S)— may be prepared by.reacting the corresponding compound of formula (X) wherein (L¹)_(b) it—C(O)— with a suitably selected thionating reagent such as P₂S₅,Lawesson's reagent, and the like, in an organic solvent such as toluene,benzene, xylene, and the like, at an elevated temperature in the rangeof from about 70° C. to about 150° C., preferably, at an elevatedtemperature in the range of from about 80° C. to about 110° C.

Compounds of formula (X) wherein (L¹)_(b) is —C₂₋₄alkenyl- may beprepared by reacting the compound of formula (XXXVIII) wherein J is Bror I with a suitably substituted stannane, or a suitably substitutedboronate, in the presence of a catalyst such as Pd(PPh₃)₄, and the like,according to known methods (for example, as disclosed in Miyaura, N.;Suzuki, A. Chem. Rev. 1995, 95, 2457; Suzuki, A. J. Organomet. Chem.1999, 576, 147).

Alternatively, compounds of formula (X) wherein (L¹)_(b) is—C₂₋₄alkenyl- may be prepared according to the process outlined inScheme 9.

Accordingly, a suitably substituted compound of formula (XXXVIIIa), acompound of formula (XXXVIII) wherein J is Br, a known compound orcompound prepared by known methods, is reacted with a suitablysubstituted compound of formula (XXXXI), wherein R³ is as defined above,preferably, wherein R³ is aryl or alkyl, a known compound or compoundprepared by known methods (for example as disclosed in Miyaura, N.;Suzuki, A. Chem. Rev. 1995, 95, 2457; Suzuki, A. J. Organomet. Chem.1999, 576,147), in the presence of a catalyst such Pd(PPh₃)₄,Pd(dppf)Cl₂, and the like, in the presence of a base such as Na₂CO₃,K₂CO₃, NaHCO₃, and the like, in a mixture of an organic solvent such astoluene, DME, THF, MeOH, and the like, and a protic solvent such aswater, and the like, at an elevated temperature in the range of fromabout 60° C. to about 150° C., preferably, at an elevated temperature inthe range of from about 100° C. to about 120° C., optionally in thepresence of microwave irradiation, to yield the corresponding compoundof formula (Xb).

Compounds of formula (X) wherein (L¹)_(b) is —C₂₋₄alkyl- may be preparedby hydrogenating the corresponding compound of formula (X) wherein(L¹)_(b) is —(C₂₋₄alkenyl)-.

Compounds of formula (X) wherein (L¹)_(b) is —CH₂— or —CH(OH)— may beprepared according to known methods, for example, by reducing thecorresponding compound of formula (X) wherein (L¹)_(b) is —C(O)— with asuitably selected reducing agent, according to known methods.

Compounds of formula (X) wherein (L¹)_(b) is —CH(OH) may alternativelybe prepared according to the process outlined in Scheme 10.

Accordingly, a suitably substituted compound of formula (XXXXII), aknown compound or compound prepared by known methods, is reacted with asuitably selected reducing agent, such as sodium borohydride, and thelike, in an organic solvent such as methanol, isopropanol, and the like,at a temperature in the range of from about room temperature to about100° C., preferably, at about room temperature, to yield thecorresponding compound of formula (XXXXIII).

The compound of formula (XXXXIII) is hydrolyzed by reacting with asuitably selected acid such as HCl, H₂SO₄, trifluoroacetic acid, and thelike, in an organic solvent such as THF, DCM, diethyl ether, and thelike, in the presence of water, to yield the corresponding compound offormula (Xc).

Compounds of formula (X) wherein (L¹)_(b) is -(hydroxy substitutedC₂₋₄alkyl)- may be prepared according to the process outlined in Scheme11.

Accordingly, a suitably substituted compound of formula (XXXXIV),wherein G is selected from chloro, bromo or iodo, a known compound orcompound prepared by known methods, is reacted with a suitablysubstituted vinyl boronate ester, a compound of formula (XXXXV) whereinR^(z) is selected from aryl or heteroaryl, a known compound or compoundprepared by known methods (for example as disclosed in Lhermitte, F.;Carboni, B. SYNLETT 1996, 377; Matsubara, S.; Otake, Y.; Hashimoto, Y.;Utimoto, K. Chem. Lett. 1999, 747; Takai, K.; Shinomiya, N.; Kaihara,H.; Yoshida, N.; Moriwake, T. SYNLETT 1995, 963; Deloux, L.; Srebnik, M.J. Org. Chem. 1994, 59, 6871), in the presence of a catalyst such asPd(PPh₃)₄, Pd(dppf)Cl₂, and the like, (Miyaura, N.; Suzuki, A. Chem.Rev. 1995, 95, 2457; Suzuki, A. J. Organomet. Chem. 1999, 576,147), inthe presence of a base such as Na₂CO₃, K₂CO₃, NaHCO₃, and the like, in amixture of an organic solvent such as toluene, DME, THF, MeOH, and thelike, and a protic solvent such as water, at an elevated temperature inthe range of from about 60° C. to about 150° C., preferably, at anelevated temperature in the range of from about 100° C. to about 120°C., optionally in the presence of microwave irradiation, to yield thecorresponding compound of formula (XXXXVI).

The compound of formula (XXXXVI) is reacted with a suitably selectedoxidizing agent such as OXONE®, and the like, (Yang, D.; Yip, Y.-C.;Jiao, G.-S.; Wong, M.-K. Org. Synth. 2000, 78, 225) in the presence of acatalyst such as tetrahydrothiopyran-4-one, and the like, in thepresence of a base such as Na₂CO₃, K₂CO₃, NaHCO₃, and the like, in amixture of an organic solvent such as MeCN, THF, and the like, and aprotic solvent such as water, to yield the corresponding compound offormula (XXXXVII).

Alternatively, the compound of formula (XXXXVI) is reacted with anoxidizing agent, such as MCPBA, (Jung, M. E.; Lam, P. Y.-S.; Mansuri, M.M.; Speltz, L. M. J. Org. Chem. 1985, 50,1087), hydrogen peroxide, andthe like, in an in the presence of a base such as Na₂CO₃, K₂CO₃, NaHCO₃,and the like, in an organic solvent such as DCM, DCE, and the like, at atemperature in the range of from about room temperature to about 100°C., preferably, at about room temperature, to yield the correspondingcompound of formula (XXXXVII).

The compound of formula (XXXXVII) is reacted with a protic acid such asptoluenesulfonic acid, methanesulfonic acid, and the like, (Bakke, J.M.; Lorentzen, G. B. Acta Chem. Scand. B 1974, 28, 650) in an organicsolvent such as benzene, toluene, and the like, at an elevatedtemperature in the range of from about 80° C. to about 150° C.,preferably, at an elevated temperature in the range of from about 80° C.to about 100° C., to yield the corresponding compound of formula(XXXXVIII)

Alternatively, the compound of formula (XXXXVII) is reacted with a Lewisacid such as BF₃.Et₂O, and the like, (Baumgarth, M.; Beier, N.; Gericke,R. J. Med. Chem. 1998, 41, 3736) in an organic solvent such as DCM,diethyl ether, and the like, at an elevated temperature in the range offrom about 40° C. to about 100° C., preferably, at an elevatedtemperature in the range of from about 40° C. to about 60° C., to yieldthe corresponding compound of formula (XXXXVIII).

The compound of formula (XXXXVIII) is reacted with a suitably selectedreducing agent, such as sodium borohydride, and the like, in an organicsolvent such as MeOH, isopropanol, and the like, at a temperature in therange of from about 0° C. to about 100° C., preferably, at about 10° C.to abour 40° C., to yield the corresponding compound of formula (Xd).One skilled in the art will recognize that in reacting the compound offormula (XXXXVIII) with a suitably selected reducing agent, the aldehydeon the compound of formula (XXXXVIII) is preferably protected to avoidreduction to the corresponding alcohol.

Compounds of formula (X) wherein (L¹)_(b) is absent (i.e. b is 0) may beprepared according to the process outlined in Scheme 12.

Accordingly, a suitably substituted compound of formula (XXXVIIIa), acompound of formula (XXXVIII) wherein J is Br, a known compound orcompound prepared by known methods (For example,4-bromo-2-nitrobenzaldehyde which may be prepared as disclosed in Jung,M. E. and Dansereau, S. M. K., Heterocycles, Vol. 39,1994, p. 767; or5-bromo-2-nitrobenzaldehyde, which may be prepared as disclosed in Hu,Y.-Z., Zhang, G., and Thummel, R. P., Org. Lett., Vol. 5, 2003, p. 2251)is reacted with a suitably substituted compound of formula (XXXXIX),wherein R³ is aryl or heteroaryl, a known compound or compound preparedby known methods, in the presence of a catalyst such Pd(PPh₃)₄,Pd(dppf)Cl₂, and the like, in the presence of a base such as Na₂CO₃,K₂CO₃, NaHCO₃, and the like, in a mixture of an organic solvent such astoluene, DME, THF, MeOH, and the like, and a protic solvent such aswater, and the like, at an elevated temperature in the range of fromabout 60° C. to about 150° C., preferably, at an elevated temperature inthe range of from about 100° C. to about 120° C., optionally in thepresence of microwave irradiation, to yield the corresponding compoundof formula (Xe).

Compounds of formula (XI) are known compounds or compounds which may beprepared by known methods. Schemes 13-17 below, outline representativeprocesses for the preparation of representative compounds of formula(XI).

For example, compounds of formula (XI) wherein Q¹ is —C(O)—NR^(A)— maybe prepared according to the processes outlined in Scheme 13.

Accordingly, a suitably substituted compound of formula (D), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (DI), a known compound orcompound prepared by known methods, in the presence of a base such asTEA, DIPEA, pyridine, and the like, in an organic solvent such as THF,DCM, chloroform, and the like, to yield the corresponding compound offormula (DII).

The compound of formula (DII) is reacted with NaCN, in an organicsolvent such as DMSO, DMF, NMP, and the like, at an elevated temperaturein the range of from about 50 to about 160° C., preferably, at anelevated temperature in the range of from about 80 to about 125° C., toyield the corresponding compound of formula (DIV).

The compound of formula (DIV) is reduced according to known methods, forexample by reacting with hydrogen gas in the presence of Raney nickel orrhodium, in an organic solvent such as methanol, ethanol, water, and thelike, to yield the corresponding compound of formula (XIa).

Alternatively, a suitably substituted compound of formula (DIII), aknown compound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (DI), a known compound orcompound prepared by known methods, in the presence of a peptidecoupling reagent such as HATU, HOBT, DIPCDI, HBTU, and the like, in thepresence of a base such as TEA, DIPEA, pyridine, and the like, in anorganic solvent such as THF, DMF, and the like, to yield thecorresponding compound of formula (DIV).

The compound of formula (DIV) is reduced according to known methods, forexample by reacting with H₂ gas, in the presence of Raney nickel orrhodium, in an organic solvent such as methanol, ethanol, water, and thelike, to yield the corresponding compound of formula (XIa).

Alternatively still, a suitably substituted compound of formula (DV),wherein Pgl is a suitable nitrogen protecting group, such as Cbz, BOC,and the like, a known compound or compound prepared by known methods, isreacted with a suitably substituted compound of formula (DI), a knowncompound or compound prepared by known methods, in the presence of apeptide coupling reagent such as HATU, HOBT, DIPCDI, HBTU, and the like,in the presence of a base such as TEA, DIPEA, pyridine, and the like, inan organic solvent such as THF, DMF, and the like, to yield thecorresponding compound of formula (DVI).

The compound of formula (DVI) is de-protected according to knownmethods, for example by hydrogenolysis (wherein PG¹ is Cbz) or acidcleavage (wherein PG¹ is BOC), to yield the corresponding compound offormula (XIa).

One skilled in the art will recognize that for compounds of formula (XI)wherein Q¹ is —C(O)—NR^(A)— and wherein the A¹ group (i.e. the—(C₁₋₄alkyl)- group) is substituted as herein defined, may be similarlyprepared according to the processes outlined in Scheme 12.

For example, compounds of formula (XI) wherein the —(C₁₋₄alkyl)- (the A¹group) is substituted at carbon atom bound directly to the core of thedesired compound of formula (I) may be prepared by substituting asuitably substituted compound of formula (DVII)

wherein R^(X) is the substituent on the A¹ group as defined herein, forthe compound of formula (DV) above.

Similarly, compounds of formula (XI) wherein alternate carbon atoms ofthe A¹ group are substituted may be similarly prepared by selecting andsubstituting suitably substituted starting reagents for the compound offormula (D), (DIII) or (DV).

Alternatively, compound of formula (XI) wherein Q¹ is —C(O)—NR^(A)— andthe A¹ group (i.e. the —(C₁₋₄alkyl)- group) is substituted at carbonatom bound directly to the nitrogen atom on the core of the desiredcompound of formula (I) may be prepared according to the processoutlined in Scheme 14.

Accordingly, a suitably substituted compound of formula (DVIII), a knowncompound or compound prepared by known methods (for example by reactingdihydro-furan-2,5-dione or dihydro-pyran-2,6-dione with a compound ofthe formula R^(X)—MgCl or R^(X)—MgBr, optionally in the presence of acatalyst such as CuI, in an organic solvent such as THF) is reacted witha suitably substituted compound of formula (DI), a known compound orcompound prepared by known methods, in the presence of a peptidecoupling reagent such as HATU, HOBT, DIPCDI, HBTU, and the like, in thepresence of a base such as TEA, DIPEA, pyridine, and the like, in anorganic solvent such as THF, DMF, and the like, to yield thecorresponding compound of formula (DIX).

The compound of formula (DIX) is then substituted for the compound offormula (XI) and further reacted according to the processes describedabove, to yield the corresponding compound of formula (I).

Compounds of formula (XI) wherein Q¹ is —NR^(A)— may be prepared byknown methods, for example, according to the process outlined in Scheme15.

Accordingly, a suitably substituted compound of formula (DX), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (DI), a known compound orcompound prepared by known methods, in the presence of a base such asTEA, DIPEA, pyridine, and the like, in an organic solvent such as THF,DMF, and the like, to yield the corresponding compound of formula (DXI).

The compound of formula (DXI) is reacted with N₂H₄, and the like, in anorganic solvent such a ethanol, DMF, and the like, to yield thecorresponding compound of formula (XIc).

One skilled in the art will recognize that compounds of formula (XI)wherein Q¹ is —NR^(A)—C(O)— may be prepared from the correspondingcompound of formula (DXI) wherein -A¹-Q¹-H is —(C₁₋₄alkyl)-NR^(A)—H, byreacting with a suitably substituted acid chloride of the formulaR²—C(O)Cl, in the presence of a base such as TEA, DIPEA, pyridine, andthe like, preferably, the base is present in amount equal to about oneequivalent, in an organic solvent such as dioxane, DCM, THF, and thelike.

One skilled in the art will further recognize that compounds of formula(XI) wherein -Q¹-R² is selected from —NR^(A)—R², —NR^(A)—C(O)R² or—NR^(A)—C(O)—R² and wherein the A¹ group (i.e. the (C₁₋₄alkyl) group))is optionally substituted, may be similarly prepared according to theprocesses outlined in Scheme 15 above, by selecting and substitutingsuitably substituted starting reagents.

Alternatively, compounds of formula (XI) wherein Q¹-R² is —NR^(A)—R² andwherein the A¹ group (i.e. the (C₁₋₄alkyl) group)) is optionallysubstituted, may be similarly prepared according to the processesoutlined in Scheme 16.

Accordingly, a suitably substituted compound of formula (DXII), a knowncompound or compound prepared by known methods, is reacted withNH(CH₃)(OCH₃), in the presence of a coupling agent such as (CH₃)₃Al (forcompounds of formula (DXII) wherein W is C₁₋₄alkyl), or a coupling agentsuch as DCC, EDC, and the like, in an organic solvent such as DCM, DMF,and the like, to yield the corresponding compound of formula (DXIII).

The compound of formula (DXIII) is reacted with a suitably substitutedcompound of formula (DXIV), a known compound or compound prepared byknown methods, in an organic solvent such as THF, diethyl ether, and thelike, to yield the corresponding compound of formula (DXV).

The compound of formula (DXV) is reacted NH₄OAc, NH₄Cl, and the like, inthe presence of a reducing agent such as NaBH₃CN, and the like, in aorganic solvent such as methanol, ethanol, and the like; or reacted withNH₄O₂CCF₃, NH₄OAc, and the like, in the presence of a reducing agentsuch as NaBH(OAc)₃, and the like, in an organic solvent such as DCE,THF, acetonitrile, and the like; to yield the corresponding compound offormula (DXVI).

The compound of formula (DXVI) is then reacted according to theprocesses disclosed herein (for Example as in Scheme 1) and de-protectedto yield the corresponding, desired compound.

One skilled in the art will recognize that the compound of formula (XId)may be further, optionally reacted according to known methods (forexample by reacting with a suitably substituted compound of the formula)to further substitute the de-protected amine as desired.

One skilled in the art will recognize that compounds of formula (XI)wherein -Q¹-R² is —NH—C(O)—R² and wherein the A¹ group (i.e. the(C₁₋₄alkyl) group)) is optionally substituted may be prepared from thecorresponding compound of formula (DXV) according to the processoutlined in Scheme 17.

Accordingly, a suitably substituted compound of formula (DXV) is isde-protected according to known methods, to yield the correspondingcompound of formula (DXVII).

The compound of formula (DXVII) is reacted with a suitably substitutedacid chloride, a compound of the formula (DXVIII), a known compound orcompound prepared by known methods, in the presence of a base such asTEA, DIPEA, pyridine, and the like, in an organic solvent such asdioxane, DCM, THF, and the like, to yield the corresponding compound offormula (DXIX).

The compound of formula (DXIX) is reacted with NH₄OAc, NH₄Cl, and thelike, in the presence of a reducing agent such as NaBH₃CN, and the like,in a organic solvent such as methanol, ethanol, and the like; or reactedwith NH₄O₂CCF₃, NH₄OAc, and the like, in the presence of a reducingagent such as NaBH(OAc)₃, and the like, in an organic solvent such asDCE, THF, acetonitrile, and the like; to yield the correspondingcompound of formula One skilled in the art will further recognize thatcompounds of formula (XI) wherein -A¹-Q¹-R² is —(C₁₋₄alkyl)-NH—C(O)—OR²,compounds of formula (XI) wherein -A¹-Q¹-R² is—(C₁₋₄alkyl)-NH—C(S)—NH—R² and compounds of formula (XI) wherein-A¹-Q¹-R² is —(C₁₋₄alkyl)-NH—C(O)—NH—R² may be similarly preparedaccording to known methods, by modifying the process described in Scheme2.

One skilled in the art will further recognize that compounds of formula(XI) wherein Q¹ is other than one of the substituent groups specificallyexemplified above, for example wherein Q¹ is selected from —O—, —S—,—OC(O)—, —NR^(A)—SO, —NR^(A)—SO₂—, —SO—NR^(A)—, —SO₂—NR^(A)—,—OC(O)—NR^(A)—, —NR^(A)—SO₂—O—, —O—SO₂—NR^(A)— or —NR^(A)—SO₂—NR^(B)—,may be similarly prepared according to known methods.

Compounds of formula (XI) wherein the A¹ group (i.e. the—(C₁₋₄alkyl)-group) is substituted at the carbon atom closest to thecore structure is substituted and wherein a single enantiomer is desired(or wherein an enantiomeric excess of a single enantiomers is desired)may alternatively be prepared by chiral separation of the correspondingracemic mixture.

Compounds of formula (XI) wherein the A¹ group (i.e. the—(C₁₋₄alkyl)-group) is substituted at the carbon atom closest to thecore structure is substituted and wherein a single enantiomer is desired(or wherein an enantiomeric excess of a single enantiomers is desired)may alternatively be prepared according to any of the process asdisclosed in Burk, M. J.; Gross, M. F.; Martinez, J. P. J. Am. Chem.Soc. 1995, 117, 9375;.Smrcina, M.; Majer, P.; Majerova, E.; Guerassina,T. A.; Eissenstat, M. A. Tetrahedron 1997, 53, 12867; and/or Hintermann,T.; Gademann, K.; Jaun, B. Seebach, D. Helv. Chim. Acta 1998, 81, 983

One skilled in the art will further recognize that the processesdescribed in Schemes 8-17 may be modified, for example, by selecting andsubstituting suitable starting materials and/or reagents, to yieldcorresponding compounds for the preparation of compounds of formula (II)and/or compounds of formula (III).

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products are listed ashaving been isolated as a residue. It will be understood by one ofordinary skill in the art that the term “residue” does not limit thephysical state in which the product was isolated and may include, forexample, a solid, an oil, a foam, a gum, a syrup, and the like.

EXAMPLE 1 3-Amino-N-cyclohexyl-N-methyl-propionamide

A mixture of 2-cyano-N-cyclohexyl-N-methyl-acetamide (3.96 g, 0.022mol), a known compound, (which may be prepared as disclosed in Osderie,Thomas S. et al. Journal of Medicinal Chemistry (1967), 10(2), 165-7;Osdene, Thomas S.; Santilli, Arthur A. U.S. Pat. No. 3,138,595) andRaney nickel (3 9) in NH₃/MeOH (300 mL) was hydrogenated at normalpressure. After 2 equivalents of hydrogen were consumed, the catalystwas removed by filtration. The filtrate was evaporated, and toluene wasadded to the residue and then evaporated to yield a residue.

EXAMPLE 23-(5-Benzoyl-2-nitro-benzylamino)-N-cyclohexyl-N-methyl-propionamide

A mixture of 5-benzoyl-2-nitro-benzaldehyde (10 g, 0.0390 mol), a knowncompound (which may be prepared as disclosed in European Patent EP371564) and 3-amino-N-cyclohexyl-N-methyl-propionamide (7.5 g, 0.0410mol) in 1,2-dichloroethane (250 mL) was stirred at room temperatureunder nitrogen. Sodium triacetoxyborohydride (8.7 g, 0.0410 mol) wasadded, and the reaction mixture was stirred for 6 h at room temperature.Saturated NaHCO₃ solution (200 mL) was then added. The organic layer wasseparated, dried, and evaporated. The resulting residue was purified bycolumn chromatography on silica gel (eluent: 99:1 CH₂Cl₂:MeOH). Thepurest fractions were combined, and the solvent was evaporated to yielda residue.

EXAMPLE 33-(2-Amino-5-benzoyl-benzylamino)-N-cyclohexyl-N-methyl-propionamide

A mixture of3-(5-benzoyl-2-nitro-benzylamino)-N-cyclohexyl-N-methyl-propionamide (9g, 0.02 mol), 10% palladium on carbon (2 g), and thiophene solution (2mL) in MeOH (250 mL) was hydrogenated until 3 equivalents of hydrogenwere consumed. The reaction mixture was filtered through Dicalite, andthe filtrate was concentrated to yield a residue.

EXAMPLE 43-(2-Amino-6-benzoyl-4H-quinazolin-3-yl)-N-cvclohexyl-N-methyl-propionamide(Compound #1)

To a solution of3-(2-amino-5-benzoyl-benzylamino)-N-cyclohexyl-N-methyl-propionamide(3.94 g, 0.0100 mol) in methanol (200 mL) was added cyanogen bromide(1.16 g, 0.0110 mol). The resulting mixture was stirred at roomtemperature over the weekend and then was heated at reflux for 5 h. Thesolvent was evaporated to yield a residue that was crystallized fromEtOAc (100 mL). The resulting precipitate was filtered and dried toyield crude product that was recrystallized from 2-propanol (50 mL) toyield the title compound,3-(2-amino-6-benzoyl-4H-quinazolin-3-yl)-N-cyclohexyl-N-methyl-propionamide.

mp 198.1° C.

EXAMPLE 5 2-(Dimethoxymethyl)-1 -nitro-4-phenoxy-benzene

A mixture of 4-chloro-2-dimethoxymethyl-1-nitrobenzene (11.55 g, 0.0500mol), phenol (4.70 g, 0.0500 mol), and potassium carbonate (8.16 g,0.0600 mol) in DMA (100 mL) was stirred at 150° C. for 6 h. Aftercooling, the reaction mixture was poured into water and treated withdiisopropyl ether. The organic layer was separated, washed with 10%aqueous KOH solution, dried (MgSO₄), filtered, and concentrated. Theresulting residue was purified by column chromatography on silica gelusing as eluent CH₂Cl₂:petroleum ether (40:60, 60:40,100:0 gradient).The product containing fractions were combined and evaporated to yield aresidue which was dissolved in CH₂Cl₂ and washed with 10% aqueous KOHsolution to remove the remaining phenol. Drying and evaporation yieldeda residue.

EXAMPLE 6 2-Nitro-5-phenoxy-benzaldehyde

To a solution of 2-(dimethoxymethyl)-1-nitro-4-phenoxy-benzene (7.4 g,0.0256 mol) in THF (80 mL) was added 12 N HCl (10 mL) and water (20 mL).The resulting mixture was stirred at room temperature for 2 days. Waterwas then added, and the mixture was extracted with diisopropyl ether.The organic layer was separated, washed with 10% aqueous NaHCO₃ solutionand then with water, dried (MgSO₄), filtered, and concentrated to yielda yellow solid.

EXAMPLE 7N-Methyl-3-(2-nitro-5-phenoxy-benzylamino)-N-phenyl-propionamide

2-Nitro-5-phenoxy-benzaldehyde (2.14 g, 0.00882 mol) was added to asolution of 3-amino-N-cyclohexyl-N-methyl-propionamide (1.5 g, 0.00882mol) in 100 mL of 1,2-dichloroethane, and the mixture was stirred at 80°C. for 1 hour. Sodium triacetoxyborohydride (2.87 g, 0.00882 mol) wasadded at room temperature, and the reaction mixture was stirred for 15h. Additional sodium triacetoxyborohydride (1 g) was added, and thereaction mixture was stirred another 20 h at room temperature. To thereaction mixture was added 10% aqueous NaOH solution (50 mL), and themixture was extracted with CH₂Cl₂. The organic layer was separated,dried (MgSO₄), filtered, and concentrated to yield a residue which waspurified by column chromatography over silica gel using 97:3 CH₂Cl₂:MeOHas the eluent. The product containing fractions were combined andevaporated to yield a side product (MW 638). The residue was furtherpurified by column chromatography over silica gel using 97:3CH₂Cl₂:MeOH. The product containing fractions were combined andevaporated to yield a residue. The fractions containing impure productwere combined and evaporated to yield a second residue, which waspurified by silica gel chromatography to yield additional desiredproduct.

EXAMPLE 83-(2-Amino-5-phenoxy-benzylamino)-N-methyl-N-phenyl-propionamide

A mixture ofN-methyl-3-(2-nitro-5-phenoxy-benzylamino)-N-phenyl-propionamide (2 g,0.0049 mol), 10% palladium on carbon (1 g), and thiophene solution (1mL) in 150 mL of MeOH was hydrogenated until 3 equivalents of hydrogenwere consumed. The reaction mixture was filtered, and the filtrate wasconcentrated. The resulting residue was purified by columnchromatography on a Biotage. The product containing fractions werecollected and concentrated to yield a residue.

EXAMPLE 93-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-N-cyclohexyl-N-methyl-propionamide(Compound # 20)

A solution of3-(2-amino-5-phenoxy-benzylamino)-N-methyl-N-phenyl-propionamide(diamine) (1.4 g, 0.0037 mol) and cyanogen bromide (0.58 g, 0.0055 mol)in 70 mL of ethanol was refluxed for 3 h. The solvent was evaporated toyield a residue, which was crystallized from EtOAc (100 mL). Theresulting precipitate was dissolved in ethanol and stirred for 3 h. Theresulting precipitate was collected by filtration, washed with ethanol,and dried to yield the title product, pure3-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-N-cyclohexyl-N-methyl-propionamide.

EXAMPLE 10(3-Dimethoxymethyl-4-nitro-phenyl)-morpholin-4-yl-phenyl-acetonitrile

NaH (0.975 mol) was washed with hexane. After the hexane was decantedoff, the NaH was stirred in DMF (1950 mL) at room temperature.Morpholin-4-yl-phenyl-acetonitrile (0.70 mol) in DMF (300 mL) was addeddropwise under N₂ gas. The reaction mixture was stirred at roomtemperature for 2 hours. The reaction mixture was cooled in an ice bathand 4-chloro-2-dimethoxymethyl-1-nitrobenzene (0.86 mol) in DMF (150 mL)was added dropwise. The reaction mixture was stirred at 0° C. for 2hours and at room temperature overnight. The reaction mixture was pouredon ice/water and extracted with diisopropyl ether. The organic layerwashed with water, dried (MgSO₄) and evaporated to yield the titlecompound as a solid.

EXAMPLE 11 (3-Dimethoxymethyl-4-nitro-phenyl)-phenyl-methanone

A solution of the residue prepared as in Example 10 (0.7 mol) in 70%acetic acid (1500 mL) was stirred and refluxed for 30 min. The reactionmixture was poured on ice/water and extracted with diisopropyl ether.The organic layer was washed with alkalic water and water. The organiclayer was dried (MgSO₄) and evaporated to a residue. The aqueous layersthat contained product were further extracted with DCM. The organiclayer was dried (MgSO₄) and evaporated to yield a residue. The residuesfrom above were purified on a glass filter over silica gel (eluent:DCM). The pure fractions were collected and evaporated to yield thetitle compound as a solid.

EXAMPLE 12 5-Benzoyl-2-nitrobenzaldehyde

A mixture of the solid prepared as in Example 11 (0.0659 mol) and 5N HCl(40 mL) in chloroform (80 mL) was stirred at room temperature overnight.Then, the reaction mixture was refluxed for 4 hours. After cooling, theorganic layer was separated. The organic layer was made alkaline byadding dropwise NH₄OH. The organic layer was washed with water, dried(MgSO₄) and evaporated. The residue was crystallized from diisopropylether/ethyl acetate (50 mL/20 mL). The precipitate was filtered off,washed with diisopropyl ether/ethyl acetate and diisopropyl ether anddried in vacuo at 50° C. to yield the title compound as a beige solid.

mp 96.7° C.

Note: The title compound may alternatively be prepared according to theprocedure disclosed in EP 0371564 A2.

EXAMPLE 13 2-amino-5-benzoylbenzaldehyde

A mixture of 5-benzoyl-2-nitrobenzaldehyde (0.01 mol) in toluene washydrogenated at room temperature and normal pressure with 5% Pd/C (2 g)as a catalyst in the presence of 4% thiophene solution (2 mL). Afteruptake of H₂ gas (3 equiv.), the catalyst was filtered off and thefiltrate was evaporated (water bath at 50° C.). The residue wasdissolved in diethyl ether (10 mL) and crystallized out at roomtemperature. The crystals were filtered off, washed with a small amountof diethyl ether and diisopropyl ether, then dried (vacuum, 40° C.) toyield the title compound as a solid.

mp 124.9° C.

EXAMPLE 14 Cyclohexanecarboxylic acid[2-(2-amino-5-benzoyl-benzylamino)-ethyl]-amide

A mixture of 2-amino-5-benzoylbenzaldehyde (0.007 mol) andcyclohexanecarboxylic acid (2-amino-ethyl)-amide (0.007 mol) in methanolwas hydrogenated at 50° C. with 10% Pd/C (0.5 g) as a catalyst in thepresence of thiophene solution (1 mL). After uptake of H₂ gas (1 equiv.)the catalyst was filtered off and the solvent evaporated. The residuewas purified by column chromatography over silica gel (Biotage column)(eluent:CH₂Cl₂:methanol gradient). The desired fractions were collectedand the solvent evaporated to yield the title compound as a residue.

EXAMPLE 15 Cyclohexanecarboxylic acid[2-(2-amino-6-benzoyl-4H-quinazolin-3-yl)-ethyl]-amide (Compound #7)

A mixture of cyclohexanecarboxylic acid[2-(2-amino-5-benzoyl-benzylamino)-ethyl]-amide (0.0032 mol) in ethanol(30 mL) was stirred at room temperature. Cyanogen bromine (0.0048 mol)was added. The reaction mixture was stirred and refluxed for 2 hours,then cooled and stirred overnight at room temperature resulting in aprecipitate. The precipitate was filtered off, washed with diisopropylether and dried to yield the title compound as a residue.

EXAMPLE 16 2-Nitro-5-phenoxy-benzaldehyde

Step A:

To a solution of 5-fluoro-2-nitro-toluene (38.2 g, 0.25 mol) in 200 mLof DMF was added phenol (23.5 g, 0.25 mol) and K₂CO₃ (43.0 g, 0.31 mol)and the mixture was heated at 140° C. overnight. The mixture was cooledto room temperature, then most of the DMF was evaporated in vacuo. Theresidue was dissolved in EtOAc, washed with water (2×) and brine andthen dried (K₂CO₃). The solution was filtered, and the solvent wasevaporated in vacuo to yield a dark brown oil. The crude product waspurified by Kugelrohr distillation, and after a small forerun (80-90°C.), 4-phenoxy-2-nitrotoluene was collected as a viscous yellow oil (mp120-130° C.) that crystallized on standing.

Step B:

A mixture of 2-nitro-5-phenoxytoluene (57.3 g, 0.25 mol) prepared inStep A above and dimethylformamide dimethyl acetal (43.1 mL, 0.324 mol)in DMF (259 mL) was heated overnight at 140° C. The mixture was cooledto room temperature, and the solvent was evaporated in vacuo. Theresidue was dissolved in THF (500 mL) and transferred to a 3L 3-neckflask equipped with an overhead stirrer. The mixture was diluted with500 mL of water, and NaIO₄ (160 g, 0.75 mol) was added in portions(slight exotherm). The mixture was stirred overnight at roomtemperature. The solids were-filtered and washed well with EtOAc. Thefiltrate was washed 3× with saturated aqueous NaHCO₃ solution, and thendried (MgSO₄). The solution was filtered and the solvent was evaporatedin vacuo. The crude product was chromatographed (10-40% CH₂Cl₂:hexane)to yield 2-nitro-5-phenoxy-benzaldehyde as a yellow crystalline solid.

EXAMPLE 17 2-Nitro-5-phenoxy-benzaldehyde

A mixture of 5-fluoro-2-nitrobenzaldehyde (15.00 g, 0.089 mol), phenol(9.12 g, 0.098 mol), and K₂CO₃ (13.5 g, 0.089 mol) in 200 mL of DMF washeated at 120° C. for 50 min. The reaction mixture was cooled andconcentrated in vacuo. To the residue was added EtOAc (500 mL) and H₂O(500 mL). The layers were separated, and the EtOAc extract wasconcentrated. The residue was purified on silica gel using 20%EtOAc-hexane as eluent. The product containing fractions were combinedand concentrated to yield a yellow oil which solidified on standing.This material was dissolved in a minimal quantity of EtOAc and hexane,and the resulting solution was cooled in a dry ice acetone bath.Filtration yielded 2-nitro-5-phenoxy-benzaldehyde as a light yellowsolid. The filtrate was concentrated in vacuo to yield additional2-nitro-5-phenoxy-benzaldehyde.

EXAMPLE 18 Cyclohexanecarboxylic acid[2-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-ethyl]-amide (Compound #111)

Step A

A solution of 2-nitro-5-phenoxybenzaldehyde (1.4 g, 5.8 mmol) andN-tert-butoxycarbonylethylenediamine (1.4 g, 8.75 mmol) in 60 mL of DCEwas stirred at room temperature for 40 minutes. Then, NaBH(OAc)₃ (1.86g, 8.75 mmol) was added, and the mixture was stirred at room temperatureovernight. The reaction was quenched by the addition of 3N NaOH. Theorganic layer was washed with brine and then was concentrated in vacuoto yield a crude product. The crude product was purified by flashchromatography (40% EtOAc/hexane) to yield a residue.

MH⁺=388

Step B

A solution of the compound prepared in Step A above (2.0 g, 5.2 mmol) in100 mL of EtOH was hydrogenated (40 psi) overnight with 10% Pd/C. Thecatalyst was removed by filtration, and the filtrate was concentrated invacuo to yield a residue.

Step C

To a solution of the residue prepared in Step B above (0.44 g, 1.18mmol) EtOH (15 mL) was added BrCN (0.13 g, 1.3 mmol). The reactionmixture was stirred at room temperature for 1 h and then heated atreflux for 3 h. The solvent was evaporated in vacuo, and the residue waspurified by reverse phase HPLC to yield a white solid.

MH⁺=383

Step D

A solution of the white solid prepared in Step C above (0.13 g, 0.28mmol) 10 mL of TFA was stirred at room temperature overnight. Thesolvent was evaporated in vacuo to yield a residue.

Step E

To a solution of the residue prepared in Step D above (0.088 g, 0.17mmol) in 5 mL of dioxane was added TEA (0.14 g, 0.41 mmol) followed bycyclohexylcarbonyl chloride (0.02 g 0.14 mmol). The reaction mixture wasstirred overnight at room temperature. The solvent was evaporated invacuo and the product was purified by reverse phase HPLC to yield thetitle compound, cyclohexanecarboxylic acid[2-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-ethyl]-amide as a white solid.

MH⁺=393

¹H NMR (300 MHz, CDCl₃): δ1.15-1.64 (m, 10H), 2.04 (m, 1H), 3.50 (m,4H), 4.57 (s, 2H), 6.88-7.41 (m, 8H), 7.87-7.90 (m, 3H).

EXAMPLE 19 Cyclohexanecarboxylic acid[2-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-2-cyclohexyl-ethyl]-amide(Compound #294)

Step A

To a suspension of N,O-dimethylhydroxylamine HCl (0.443 g, 4.5 mmol) in100 mL of CH₂Cl₂ cooled to −10° C., was added a 1.2M solution ofAl(CH₃)₃ in hexane (2.19 mL, 4.39 mmol). The resulting reaction mixturewas warmed to room temperature and stirred for 30 min, and thenre-cooled to 0° C. A solution of N-(tert-butoxycarbonyl) glycine methylester (0.23 g 1.46 mmol) in 2 mL of CH₂Cl₂ was then added. The reactionmixture was allowed to warm to room temperature and stirred overnight.The reaction was quenched by addition of 1 M KHSO₄ (5 mL), and theaqueous layer was extracted with two additional portions of CH₂Cl₂. Thecombined extracts were washed with brine and dried over Na₂SO₄. Thesolution was filtered, and the solvent was evaporated in vacuo to yielda white solid.

Step B

To a solution of the white solid prepared as in Step A (2.8 g, 12.8mmol) in 50 mL of THF cooled in an ice bath, was added 2.0M cyclohexylmagnesium chloride solution in diethyl ether (38.4 mL, 76.8 mmol) andthe reaction mixture was warmed to room temperature and stirred for 1 h.The reaction mixture was quenched with saturated NH₄Cl and extractedwith EtOAc (3×). The combined organic layers were washed with brine anddried over MgSO₄. The solution was filtered and the solvent wasevaporated in vacuo to yield crude product which was used in thefollowing step without further purification.

Step C

To a solution of the crude product prepared in Step B above (3.5 g) in40 mL of MeOH was added NH₄OAc (24.0 g, 0.33 mol), and the mixture wasstirred at room temperature for 5 h. Next, NaCNBH₃ (1.2 g, 19.0 mmol)was added and the reaction was stirred overnight at room temperature.The solvent was evaporated in vacuo, and the residue was dissolved inwater and extracted with Et₂O (3×). The combined extracts were washedwith brine and the solvent was evaporated in vacuo to yield an oil.

Step D

To a solution of 2-nitro-5-phenoxybenzaldehyde (1.56 g, 6.4 mmol) andthe crude product prepared in Step C above in 100 mL of CH₂Cl₂ was addedNaBH(OAc)₃ (2.0 g, 9.6 mmol). The reaction mixture was stirred overnightat room temperature. The reaction was quenched with 2N NaOH, and thelayers were separated. The aqueous layer was extracted with CH₂Cl₂ (2×).The combined extracts were washed with brine and dried over MgSO₄. Thesolution was filtered and the solvent was evaporated in vacuo to yieldan oil. Flash chromatography (1 to 10% EtOAc in CH₂Cl₂) of the oi!yielded a residue.

MH⁺=470

Step E

A solution of the product prepared in Step D above (1.03 g, 2.19 mmol)and Pd/C (200 mg) in 100 mL of EtOH was hydrogenated at 40 psi for 3 h.The solution was filtered through Dicalite, and the filtrate wasconcentrated to a 30 mL solution.

Step F

To the solution prepared in Step E was added BrCN (0.26 g, 2.5 mmol),and the reaction mixture was stirred overnight at room temperature. Thenext day, the reaction mixture was heated at reflux for 90 min, and thenthe solvent was evaporated in vacuo. The crude product was purified byreverse phase HPLC to yield an off-white solid.

MH⁺=465

Step G

A solution of the off-white solid prepared in Step F above (0.86 g, 1.49mmol) in 15 mL of TFA was stirred at room temperature for 5 h. Theexcess TFA was evaporated to yield an oil.

Step H

To a solution of the oil prepared in Step G. above (0.06 g, 0.12 mmol)in 7 mL of dioxane was added TEA (37.6 mg, 0.37 mmol) followed byaddition of cyclohexylcarbonyl chloride (0.018 g, 0.12 mmol). Thereaction mixture was stirred overnight at room temperature. The solventwas evaporated in vacuo yield the title compound, cyclohexanecarboxylicacid [2-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-2-cyclohexyl-ethyl]-amideas a white solid.

MH⁺=475

¹H NMR (300 MHz, DMSO-d₆): δ1.13-2.51 (m, 22H), 3.43 (m, 2H), 3.86(m,1H), 4.40 (d, J=15.2 Hz, 1H), 4.41 (d, J=15.5 Hz,1H), 6.93-7.41 (m,8H), 7.77 (m, 3H).

EXAMPLE 20 Cyclohexanecarboxylic acid[2-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-2-(R)-cyclohexyl-ethyl]-amide(Compound #485)

Step A

To a solution of tert-butoxycarbonylamino-(R)-cyclohexyl-acetic acid(2.57 g, 10.0 mmol), (Boc)₂O (2.83 g, 13.0 mmol), and NH₄CO₃ (1.0 g,12.6 mmol) in 50 mL of acetonitrile was added 0.05 mL of pyridine, andthe reaction mixture was stirred at room temperature overnight. Water(50 mL) was added, and the reaction mixture was concentrated to ½ theoriginal volume. The suspension was filtered, and a white solid wascollected and washed with water.

Step B

The white solid prepared in Step A above, (0.65 g) was suspended inCH₂Cl₂ (20 mL), and 10 mL of TFA was added. The reaction mixture wasstirred at room temperature for 3 h. The solvent was evaporated in vacuoto yield a residue.

Step C

A solution of the residue prepared in Step B above (0.66 g, 2.44 mmol)and 2-nitro-5-phenoxybenzaldehyde (0.4 g, 1.63 mmol) in 40 mL of THF wasstirred for 30 min. Then NaBH(OAc)₃ (0.521 g, 2.44 mmol) was added, andthe reaction mixture was stirred overnight at room temperature. Thereaction mixture was quenched with 1 N NaOH and extracted with EtOAc(3×). The combined extracts were washed with brine and dried over MgSO₄.The solution was filtered, and the filtrate was evaporated in vacuo toyield a residue.

Step D

To a solution of the residue prepared in Step C above (0.31 g, 0.8 mmol)in 10 mL of THF was added 4.0 mL of BH₃.THF, and the mixture was heatedat reflux overnight. The reaction was cooled in ice and quenched with1.5 mL of HCl, and the resultant mixture heated at reflux for 90 min.The solution was basified with 3N NaOH and extracted with CH₂Cl₂ (3×).The combined extracts were washed with brine, dried over Na₂SO₄,filtered and then evaporated in vacuo to yield an oil. Flashchromatography (3-5% MeOH in CHCl₃) yielded a yellow oil.

MH⁺=370

Step E

To a solution of the yellow oil prepared in Step D above (0.44 g, 1.2mmol) and TEA (0.35 mL, 2.5 mmol) in CH₂Cl₂ (10 mL) was addedcyclohexanecarbonyl chloride (0.21 g, 1.4 mmol). The resulting mixturewas stirred overnight at room temperature. Next, the reaction mixturewas diluted with additional CH₂Cl₂ and washed with water, and thenbrine, and then dried over Na₂SO₄. The solution was filtered, and thesolvent was evaporated in vacuo to yield a crude product. Flashchromatography of the crude product (5-15% EtOAc in CH₂Cl₂) yielded ayellow foam.

MH⁺=480

Step F

A solution of the yellow foam prepared in Step E above (0.78 g, 1.63mmol) in 100 mL of EtOH and 30 mL of THF was hydrogenated (40 psi)overnight with 10% Pd/C. The catalyst was removed by filtration and BrCN(0.19 g, 1.63 mmol) was added. The reaction mixture was stirred at roomtemperature. The solvent was evaporated in vacuo and the residue waspurified by reverse phase HPLC to yield the title compound as a brownsolid.

MH⁺=475

EXAMPLE 214-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4,N-dicyclohexyl-N-methyl-butyramide(Compound #85)

Step A

A solution of succinic anhydride (1 g, 0.01 mol) and CuI (0.2 g, 0.001mol) in THF (20 mL) was cooled to −20° C. Cyclohexyl magnesium chloride(2.0M in diethyl ether, 6 mL, 0.012 mol) was added slowly to thereaction mixture. (A purple color formed, but it disappeared after theaddition was, finished.) The cooling bath was removed, and the reactionmixture was stirred one hour at room temperature. H₂O (50 mL) and HCl (1N, 30 mL) were then added to the reaction mixture. A precipitate formedwhich was collected by filtration. CH₂Cl₂ (200 mL) was added into thefiltrate. The layers were separated; the organic layer was washed withsaturated Na₂SO₃ solution and NaCl solution. The organic layer was driedwith MgSO₄ and evaporated to yield a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.23-1.33 (m, 6H), 1.65-1.88 (m, 4H), 2.40 (m,1H), 2.59-2.64 (m, 4H).

Step B

To a solution of the colorless oil prepared in Step A above (1.1 g, 6mmol) in CH₂Cl2 (50 mL), was added isobutyl chloroformate (1 mL, 6.3mmol) at 0° C. followed by addition of TEA (2.5 mL, 18 mmol) andN-methylcyclohexylamine (1 mL, 6.6 mmol). The reaction mixture wasstirred at room temperature overnight. NaCl solution (100 mL) was thenadded. The layers were separated, and the aqueous layer was extractedwith CH₂Cl₂. The organic layers were combined, dried with MgSO₄, andevaporated. Purification by flash column chromatography (1:1hexane:EtOAc) yielded a brown oil.

MH⁺280.1

¹H NMR (300 MHz, CDCl₃): δ1.23-1.78 (m, 21H), 2.5 (m, 1H), 2.58-2.8 (m,4H), 2.85 (s, 3H), 3.66 (m, 0.4×1H), 4.39 (m, 0.6×1H).

Step C

To a solution of NH₄OAc (0.83 g, 11 mmol) and sodium cyanoborohydride(0.045 g, 8 mmol) in MeOH (20 mL) was slowly added a solution of thebrown oil prepared in Step B above (0.2 g, 0.7 mmol) in MeOH (5 mL). Thereaction mixture was then stirred at room temperature overnight. TheMeOH was evaporated, and CH₂Cl₂ (100 mL) was added followed by 1 N HCl(5 mL). The mixture was stirred 5 min, and then basified with 1 N NaOH(6 mL). The CH₂Cl₂ layer was dried with MgSO₄, and then evaporated toyield an oil.

MH⁺281.1

¹H NMR (300 MHz, CDCl₃): δ1.0-1.75 (m, 21H), 2.2-2.3 (m, 1H), 2.4-2.7(m, 4H), 2.77 (s, 3H), 3.6 (m, 0.4×1H), 4.3 (m, 0.6×1H).

Step D

To a solution of the oil prepared in Step C above (0.3 g, 1.1 mmol),2-nitro-5-phenoxybenzaldehyde (0.27 g, 1.1 mmol), and acetic acid (0.07mL, 1.1 mmol) in CH₂Cl₂ (10 mL) was added NaCNBH₃ (0.07 9, 1.2 mmol).The reaction mixture was then stirred at room temperaturefor 8 h. 1 NHCl (10 mL) was then added, and the reaction mixture was stirred for 5min and then was basified by 1 N NaOH (15 mL). The solution wasextracted with CH₂Cl₂ (50 mL×2). The organic layer was dried with MgSO₄and evaporated to yield an oil which was purified on a column (1:1hexane:EtOAc) to yield a yellow oil.

MH⁺508.5

¹H NMR (300 MHz, CDCl₃): δ1.0-1.8 (m, 24H), 2.2-2.3 (m, 2H), 2.78 (s,0.4×3H), 2.80(s, 0.6×3H), 3.57 (m, 0.4×1H), 4.0 (m, 2H), 4.5 (m, 1H),4.37 (m, 0.6×1H), 6.86. (m, 1H), 7.07 (d, J=8.33 Hz, 2H), 7.2-7.38 (m,2H), 7.42-7.44 (m, 2H), 7.97 (d, J=8.9 Hz, 1H).

Step E

To a solution of the yellow oil prepared in Step D above (0.34 g, 6.7mmol) in MeOH (10 mL) was added 0.05 g of 10% Pd on activated carbonunder N₂. The mixture was subjected to hydrogenation at 30 psi for onehour. The catalyst was filtered out, and the MeOH was evaporated toyield an oil.

MH⁺478.4

¹H NMR (300 MHz, CDCl₃): δ1.1-1.77 (m, 24H), 2.05-2.19 (m, 2H), 2.78 (s,0.4×3H), 2.79 (s, 0.6×3H), 3.5 (m, 0.4×1H), 3.75 (s, 2H), 4.44 (m,0.6×1H), 6.7 (d, J=8.04 Hz, 1H); 6.8 (m, 2H), 6.93 (d, J=7.9 Hz, 1H),7.02 (t, J=7.3 Hz, 1H), 7.3 (m, 3H).

Step F

A mixture of the oil prepared in Step E above (0.2 g, 0.4 mmol) and BrCN(0.044 g, 0.4 mmol) was refluxed in EtOH (10 mL) overnight. The EtOH wasevaporated. Diethyl ether (1 mL) and hexane (5 mL) were added to theresidue, and the mixture was stirred at room temperature for 30 min. Thesuspension was filtered, and the title compound was collected as a solidHBr salt.

MH⁺503.7

¹H NMR (300 MHz, CD₃OD): δ1.1-1.9 (m, 22H), 2.15-2.28 (m, 2H), 2.5 (m,1H) 2.74 (s, 0.4×3H), 2.78 (s, 0.6×3H), 3.47 (m, 0.4×1H), 3.97 (m, 1H),4.3 (m, 0.6×1H), 4.4 (m, 2H), 6.9-7.1 (m, 5H), 7.12 (m, 1H), 7.35 (t,J=7.76 Hz, 2H).

EXAMPLE 224-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4-(S)-,N-dicyclohexyl-N-methyl-butyramide(Compound #346)

Step A

To an ice cooled solution of Boc-D-cyclohexylglycine (3.7 g, 0.014 mol),HOBT (2.5 g, 0.018 mol) and N,O-dimethylhydroxylamine·HCl (1.8 g, 0.019mol) in CH₂Cl₂ (100 mL) was added TEA (3.9 mL, 0.028 mol) followed byaddition of 1,3-dimethylamino propyl-3-ethylcarbodiimide (EDC, 3.6 g,0.018 mol). The mixture was warmed to room temperature and stirredovernight. EtOAc (300 mL) was then added to the reaction mixture. Thereaction mixture was washed with citric acid solution, aqueous NaHCO₃solution, and NaCl solution. The organic layer was dried with MgSO₄ andevaporated to yield an oil. The crude oil was used in the following stepwithout further purification.

MH⁺301.1

¹H NMR (300 MHz, CDCl₃): δ0.93-1.07 (m, 4H), 1.36 (s, 9H), 1.54-1.68 (m,6H), 3.15 (s, 3H), 3.71 (s, 3H), 4.51 (m, 1H), 5.06 (m, 1H).

Step B

To an ice cooled solution of the oil prepared in Step A above (4.6 g,0.015 mol) in THF (200 mL) was slowly added LiAlH₄ (1 M in THF, 18 mL).The ice bath was removed, and the reaction mixture was stirred at roomtemperature for 30 min and then was cooled to 0° C. again. A solution ofNaHSO₄ in water (5 mL) was then added slowly to the reaction mixturewhile maintaining the temperature below 5° C. The mixture was extractedwith EtOAc (200 mL×2), and the combined organic layers were washed withdilute citric acid solution, saturated aqueous NaHCO₃, and saturatedaqueous NaCl solution, and then dried with Na₂SO₄ and evaporated toyield a colorless oil. The crude oil was used in the following stepwithout further purification.

MH⁺242.1

¹H NMR (300 MHz, CDCl₃): δ0.93-1.07 (m, 4H), 1.38 (s, 9H),, 1.54-1.68(m, 6H), 4.16 (m, 1H), 5.02 (m, 1H), 9.7 (m, 1H).

Step C

To an ice cooled solution of triethylphosphonoacetate (6.3 mL, 0.039mol) in THF (300 mL) was added NaH (60% dispersion in mineral oil, 1 g,0.025 mol) in portions. The resulting mixture was stirred at roomtemperature for 30 minutes and then was cooled to 0° C. again. Asolution of the oil prepared in Step B above (3.1 g, 0.013 mol) in THF(50 mL) was then added. The reaction mixture was stirred for 5 min at 0°C. and then for another 20 min at room temperature. The reaction mixturewas quenched with water, and aqueous NaCl solution was added. Thereaction mixture was extracted with EtOAc (200 mL×2), dried with MgSO₄,and evaporated. The crude product was purified by column chromatography(1:1 EtOAc:heptane) to yield an oil, which turned into a white solidupon standing.

¹H NMR (300 MHz, CDCl₃): δ0.93-1.07 (m, 4H), 1.3 (t, J=7.3 Hz, 3H), 1.40(s, 9H), 1.6-1.85 (m, 6H), 4.1 (m, 1H), 4.2 (m, 2H), 4.5 (m, 1H), 5.86(dd, J=15.6 Hz, J=1.57 Hz, 1H), 5.86 (dd, J=15.6, 5.5 Hz, 1H).

Step D

To a solution of the white solid prepared in Step C above (4.0 g, 0.013mol) in MeOH (50 mL) was added 0.4 g of 10% Pd/C under N₂. The reactionmixture was hydrogenated at 10 psi for one hour. The catalyst wasremoved by filtration, and the MeOH was evaporated to yield a solid.

MH⁺314.2

¹H NMR (300 MHz, CDCl₃): δ0.96-1.2 (m, 6H), 1.25 (t, J=7.1Hz, 3H), 1.43(s, 9H), 1.55-1.85 (m, 6H), 2.2 (m, 2H), 3.4 (m, 1H), 4.1 (m, 2H), 4.32(m, 1H).

Step E

A solution of the solid prepared in Step D above (3.5 g, 0.012 mol) andLiOH (0.29 g, 0.012 mol) in THF:H₂O (30 mL:30 mL) was stirred at roomtemperature overnight. Citric acid (2.8 g, 0.014 mol) in H₂O (10 mL) wasadded. The reaction mixture was extracted with EtOAc (100mL×2), driedwith MgSO₄, and evaporated to yield a solid.

M⁻284.1

¹H NMR (300 MHz, CDCl₃): δ0.96-1.1 (m, 6H), 1.36 (s, 9H), 1.5-1.8 (m,6H), 2.3 (m, 2H), 3.33 (m, 1H), 4.22 (m, 1H).

Step F

To an ice cooled solution of the solid prepared in Step E above (3.4 g,0.012 mol), HOBT (2.1 g, 0.015 mol) and N-methylcyclohexylamine (2 mL,0.015 mol) in CH₂Cl₂ (100 mL) was added TEA (3.3 mL, 0.024 mol) followedby addition of EDC (2.9 g, 0.015 mol). The reaction mixture was warmedto room temperature and stirred overnight. EtOAc (300 mL) was added tothe reaction mixture. The resulting solution was washed with aqueouscitric acid solution, aqueous NaHCO₃ solution, and aqueous NaClsolution. The organic layer was dried with MgSO₄ and evaporated to yielda light brown oil. The crude oil product was used in the following stepwithout further purification.

MH⁺381.3

¹H NMR (300 MHz, CDCl₃): δ0.96-1.37 (m, 12H), 1.42 (d, J=1.7 Hz, 9H),1.63-1.84 (m, 13H), 2.8 (s, 3H), 3.4 (m, 1H), 3.52 (m, 0.4×1H), 4.48 (m,0.6×1H).

Step G

A solution of the oil prepared in Step F above (1 g, 2.6 mmol) in b20%TFA:CH₂Cl₂ (50 mL) was stirred at room temperature for 1 hour. Thesolvent and most of the TFA was evaporated under reduced pressure. EtOAc(100 mL) was added to the residue. The resulting solution was washedwith aqueous NaHCO₃ solution and NaCl solution, then dried with MgSO₄,and evaporated to yield a brown oil.

MH⁺281.2

¹H NMR (300 MHz, CDCl₃): δ1.1-1.9 (m, 25H), 2.5 (m, 1H), 2.79 (s,0.4×3H), 2.85 (s, 0.6×3H), 3.5 (m, 0.4×1H), 4.3 (m, 0.6×1H).

Step H

To a solution of the oil prepared in Step G above (0.6 g, 2.1 mmol),2-nitro-5-phenoxybenzaldehyde (0.6 g, 2.3 mmol) and acetic acid (0.15mL, 2.1 mmol) in DCE (50 mL), was added NaBH₃CN (0.2 g, 3.2 mmol). Thereaction mixture was stirred at room temperature overnight, and then 1 NNaOH (10 mL) was added. The reaction mixture was extracted with CH₂Cl₂(50mL×2C. The combined organic layers were dried with MgSO₄ andevaporated to yield a residue which was purified by columnchromatography (1:1 hexane:EtOAc) to yield an oil.

MH⁺508.5

¹H NMR (300 MHz, CDCl₃): δ0.96-1.99 (m, 23H), 2.34(m, 3H), 2.79 (s,0.4×3H), 2.79. (s, 0.6×3H), 3.59 (m, 0.4×1H), 4.0 (m, 2H), 4.4 (m,0.6×1H), 6.83 (m, 1H), 7.07 (d, J=8.28 Hz, 2H), 7.2 (d, J=7.5 Hz, 2H),7.43 (t, J=8.24 Hz, 2H), 7.97 (d, J=8.25 Hz, 1H).

Step I

To a solution of the oil prepared in Step H above (0.78 g, 1.5 mmol) inMeOH (50 mL), was added 0.1 g 10% Pd/C under N₂. The reaction mixturewas hydrogenated at 30 psi for one hour. The catalyst was removed byfiltration, and the MeOH was evaporated. Preparative TLC yielded an oil.

MH⁺478.6

¹H NMR (300 MHz, CDCl₃): δ0.96-2.0 (m, 23H), 2.3 (m, 3H), 2.78 (s,0.4×3H), 2.79 (s, 0.6×3H), 3.75 (m, 0.4×1H), 3.75 (s, 2H), 4.42 (m,0.6×1H), 6.64 (dd, J=1.5 Hz, J=8.27 Hz, 1H), 6.78 (m, 2H), 6.89 (d,J=7.84 Hz, 2H), 6.97 (t, J=6.43 Hz, 1H), 7.25 (m, 2H).

Step J

A mixture of the oil prepared in Step I above (0.56 g, 1.2 mmol) andBrCN (0.13 g, 1.23 mmol) in EtOH (20 mL) was stirred at room temperatureovernight. The EtOH was evaporated, and diethyl ether (50 mL) was added.The reaction mixture was stirred at room temperature for 30 min and thenwas filtered to yield the title compound as its HBr salt as a lightbrown solid.

MH⁺503.7

¹H NMR (300 MHz, CDCl₃): δ0.9-2.18 (m, 25H), 2.5-2.6 (m, 1H), 2.81 (s,0.4×3H), 2.87 (s, 0.6×3H), 3.51 (m, 0.4×1H), 4.16 (m, 2H), 4.3 (m,0.6×1H), 6.72 (s, 1H), 6.91-6.97 (m, 2H), 7.11 (t, J=7.4 Hz, 1H), 7.25(d, J=10 Hz, 2H), 7.31 (t, J=7.6 Hz, 2H).

EXAMPLE 234-[2-Amino-6-(2-methoxy-phenyl)-4H-quinazolin-3-yl]-4-(S)-cyclohexyl-N-methyl-N-phenethyl-butyramide(Compound #721)

Step A

D-Benzyloxycarbonylamino-cyclohexyl-acetic acid (13.3 g, 45.6 mmol),HOBT (6.8 g, 50.1 mmol), and N,O-dimethylhydroxylamine hydrochloride(4.9 g, 50.1 mmol) were dissolved in CH₂Cl₂ (50 mL) with stirring. Theresulting solution was cooled in an ice-bath, and then TEA (13.3 mL,95.7 mmol) and DCC (50.1 mL, 50.1 mmol, 1 M in CH₂Cl₂) were added. Thereaction mixture was stirred at 0° C. for 1 h, then at room temperaturefor 4 h, and again cooled to 0° C. The resulting white precipitate(dicyclohexylurea) was filtered off, and the filtrate washed with 1 NNaOH (2×), 10% citric acid (aqueous) (2×), and brine. The organic layerwas dried (Na₂SO₄) and concentrated. Column chromatography (10%EtOAc:heptane to 60% EtOAc:heptane) yielded a white solid.

(M+H): 355.2

Step B

To an ice-bath cooled solution of the solid prepared in Step A above(14.1 g, 0.042 mol) in Et₂O (300 mL) was added LiAlH₄ (53 mL, 0.053mmol, 1 M in THF). The reaction mixture was stirred for 5 minutes. Thenthe cooling bath was removed, and the reaction mixture was stirred anadditional 30 minutes while warming to room temperature before asolution of NaHSO₄ (8.9 g, 73.8 mmol) in H₂O (0.33M) was added. Thelayers were separated, and the aqueous layer was extracted with Et₂O(3×100 mL). The organic layer was washed with 1 N HCl (3×50 mL),saturated aqueous NaHCO₃ solution (50 mL), and brine (50 mL), and thendried (Na₂SO₄), and concentrated. The resulting product, an oil, wasstored at −20° C. and used within 1 h without further purification.

(M+H): 276.2

Step C

(Dimethoxy-phosphoryl)-acetic acid tert-butyl ester (25 mL, 126 mmol)was dissolved in THF (400 mL) and cooled in an ice-bath with stirring.The addition of NaH (3.4 g, 84 mmol, 60% dispersion in mineral oil) ledto a gelatinous mass. The cooling bath was removed and then the slurrywas heated and stirred at 30° C. for 20 minutes. The reaction mixturewas cooled again in an ice-bath, and a solution of the product preparedin Step B above (˜42 mmol) in THF (250 mL) was added. The reactionmixture was stirred for 5 minutes at 0° C. and then for 35 minutes whilewarming to room temperature. The.reaction mixture was quenched withbrine (250 mL). EtOAc (250 mL) was then added, and the organic layer wasseparated. The aqueous layer was extracted with EtOAc (2×100 mL), dried(Na₂SO₄), and concentrated. Column chromatography (heptane to 30%EtOAc:heptane) yielded a white solid.

(M+H): 374.2

Step D

To a nitrogen degassed/blanked solution of the white solid prepared inStep C above (9.55 g, 25.5 mmol) in MeOH (200 mL) was added 10% Pd/C (1g) in water (1.5 mL). The reaction mixture was evacuated and flushedthree times with H₂, and then shaken on a Parr apparatus at roomtemperature for 3 h under H₂ (38 psi). The reaction mixture was filteredthrough Celite® and concentrated under reduced pressure to yield a whitesolid that was used without further purification.

(M+H): 242.2

Step E

To a round-bottomed flask containing the white solid prepared in Step Dabove (5.5 g, 22.8 mmol) in DCE (150 mL) was added5-bromo-2-nitrobenzaldehyde (5.24 g, 22.8 mmol). After stirring at roomtemperature for 30 minutes, NaBH(OAc)₃ (9.7 g, 45.6 mmbl) was added, andthe reaction mixture was stirred at room temperature for 18 h. Thereaction was quenched with 1 N NaOH (100 mL). The layers were separated,and the aqueous layer was extracted with DCM (3×25 mL). The combinedorganic layers were dried over MgSO₄, filtered, and concentrated invacuo to constant weight. Column chromatography (heptanes to 15%EtOAc/heptanes) yielded a yellow oil.

(M+H): 455.2

Step F

To a stirred solution of the yellow oil prepared in Step E above (4 g,8.8 mmol) in DCM (50 mL) was added TFA (50 mL). The resulting solutionwas stirred for 2 h at room temperature, concentrated to a residue,stored for 2 h at <1 mmHg, and used in the following step withoutfurther purification.

(M+H): 399.1

Step G

To a −10° C. solution of the residue prepared in Step F above (8.8 mmol)in THF (50 mL) and water (30 mL) was added 4N NaOH (10 mL, 40 mmol) anddi-tert-butyl dicarbonate (8.1 mL, 35.2 mmol). The cooling bath wasremoved, and the solution was heated to 40° C. with stirring for 20 h.The solution was concentrated to the aqueous layer, cooled to 0° C., andthe pH was adjusted to 2 with 2N HCl. The aqueous layer was extractedwith DCM (3×30 mL) and the combined organic layers were dried andconcentrated. Column chromatography (heptanes to 30% EtOAc:heptanes)yielded an off-white solid that was used in the following step withoutfurther purification.

(M+H): 499.1

Step H

To a microwave vessel containing the off-white solid prepared in Step Gabove (50 mg, 0.1 mmol) in DCM (0.5 mL) was added TEA (0.11 mL, 0.8mmol), N-methylphenethylamine (27 mg, 0.2 mmol) and2-chloro-1,3-dimethylimidazolium chloride (43 mg, 0.25 mol) in DCM (0.5mL). The resulting solution was stirred at room temperature for 24 h,quenched with water (0.1 mL), and then concentrated under vacuum toyield a residue that was used directly without further purification.

Step I

To the residue prepared in Step H above was added 2-methoxyphenylboronicacid (23 mg, 0.15 mmol) in EtOH (0.5 mL), potassium carbonate (21 mg,0.15 mmol) in water (0.05 mL) and bis(diphenylphosphino)ferrocenedichloropalladium (8.2 mg, 0.01 mmol). The reaction mixture was degassedwith nitrogen for 1 minute and then irradiated (μw) at 120° C. for 6minutes. The residue was suspended in EtOAc, loaded on a 1 g silica SPEcartridge and then eluted with 15 mL of EtOAc. The eluent wasconcentrated in vacuo to yield a residue that was used directly in thefollowing step without further purification.

Step J

To the residue prepared in Step I above was added NH₄Cl (27 mg, 0.5mmol) in EtOH (0.65 mL) and zinc dust (131 mg, 2.0 mmol). The reactionmixture was irradiated (μw) at 80° C. for 10 minutes, cooled to roomtemperature, and filtered through a 70 micron polypropylene frit andused directly as a solution in the following step.

Step K

To the EtOH solution prepared in Step J above was added cyanogen bromide(0.1 mL, 0.5 mmol, 5M in acetonitrile), and the resulting solution wasstirred for 36 h at room temperature. The reaction was quenched with 3MNaOH (0.1 mL), was stirred for 5 minutes and then concentrated in vacuo.The resulting residue was suspended in EtOAc with 1% TEA and loaded on a2 g silica SPE cartridge and then eluted with 15 ml of EtOAc with 1%TEA. The eluent was concentrated in vacuo. The resulting residue waspurified by preparative RP-HPLC to yield the title compound as a tansolid as the corresponding TFA salt.

(M+H): δ39.3

EXAMPLE 24 Cyclopentanecarboxylic acid[2-(2-amino-6-o-tolyl-4H-quinazolin-3-yl)-ethyl]-amide (Compound #657)

Step A

To a single-neck 1-L round bottom flask was charged concentratedsulfuric acid (440 mL). The flask was chilled in an ice-water bath, andpotassium nitrate (57.3 g, 0.567 mol) was added slowly in one portion,and the reaction mixture was stirred for 10 min. 3-Bromobenzaldehyde(100 g, 0.540 mol) was then added over a 15 min period, and the reactionmixture was stirred in the ice-water bath for 45 min. The reactionmixture was poured onto 2 L of crushed ice, and the ice was allowed tomelt while stirring. The aqueous slurry was extracted withdichloromethane (3×400 mL), and the combined organic phases were washedwith brine (200 mL), dried (MgSO₄), and concentrated in vacuo to yield asolid (a mixture of the desired product as well as other nitrationisomers). This material was split into two portions, and each portionwas dissolved in dichloromethane/heptane (2:1, 400 mL) and loaded onto aBiotage 75L (800 g silica gel) column. The columns were eluted withheptane (2 L) and 1:19 ethyl acetate-heptane (10 L) to yield the desiredcompound as a solid.

mp 69-71° C.

Elemental analysis for C₇H₄BrNO₃:

Calc'd: % C, 36.55; % H, 1.74; % N, 6.09; % Br, 34.74.

Found: % C, 36.68; % H, 1.68; % N, 5.88; % Br, 35.01.

HPLC: R_(t)=3.273 min; ABZ+PLUS, 3 μm, 2.1×50 mm. Gradient: A=water(0.1% TFA), B=MeCN (0.1% TFA)@0.75 mL/min. Initial: A:B, 90:10.t=0.00-4.00 min (A:B, 10:90), t=4.00-4.10 min (A:B, 0:100), t=4.10-6.00min (A:B, 0:100).

Step B

A three-neck 2 L round bottom flask was charged with the solid preparedin Step A above (30 g, 0.130 mol), 2-(amino-ethyl)-carbamic acidtert-butyl ester (20.9 g, 0.130 mol), and DCE (700 mL). The reactionmixture was stirred for 1 h, and then NaBH(OAc)₃ (68.9 g, 0.325 mol) wasadded. The reaction mixture was heated at 40° C. (exotherm observed, 47°C.) for 3.5 h. The reaction mixture was then cooled to 30° C. andquenched with 3M sodium hydroxide (exotherm observed, 39° C.). Thereaction mixture was diluted with water (500 mL), and the layers wereseparated. The aqueous phase was extracted with dichloromethane (3×400mL), and the combined organic phases were dried (MgSO₄) and concentratedin vacuo to yield crude product as a residual oil. The residual oil wasdissolved in 1:2 heptane-dichloromethane (400 mL) and loaded onto aBiotage 75L column (800 g silica gel). The column was eluted withheptane (4 L), then ethyl acetate-heptane, 1:9 (2 L), 1:4 (4 L), 2:3 (2L), and 1:1 (4 L) to yield first an unidentified by-product (4 g,18514-163B) followed by the desired product as an oil that solidified toa yellow solid upon standing.

mp 43-46° C.

Mass spectrum (Electrospray, positive mode): m/z=373/375 (M⁺) HPLC:R_(t)=2.321 min; ABZ+PLUS, 3 μm, 2.1×50 mm. gradient: A=water (0.1%TFA), B=MeCN (0.1% TFA)@0.75 mL/min. initial: A:B, 90:10. t=0.00-4.00min (A:B, 10:90), t=4.00-4.10 min (A:B, 0:100), t=4.10-6.00 min (A:B,0:100)

Step C

A 2 L Parr shaker bottle was charged with a slurry of 3.0 g of 5%platinum (sulfided) on carbon in tetrahydrofuran (25 mL) followed by asolution of the yellow solid prepared in Step B above (27.9 g, 74.5mmol) in THF (600 mL). The bottle was agitated under hydrogen gas (20-25psi) for 5 h. The system required frequent re-pressurization during theinitial 30 minutes of the reaction. The catalyst was removed byfiltration through Celite®, and the filtrate was concentrated to yield aresidue. The residue was used without further purification.

Mass Spectrum (Electrospray, positive mode): m/z=343/345 (M⁺)

HPLC: R_(t)=2.426 min; ABZ+PLUS, 3 μm, 2.1×50 mm. Gradient: A=water(0.1% TFA), B=MeCN (0.1% TFA)@0.75 mL/min. Initial: A:B, 90:10.t=0.00-4.00 min (A:B, 10:90), t=4.00-4.10 min (A:B, 0:100), t=4.10-6.00min (A:B, 0:100)

Step D

A 3 L one-necked flask equipped with magnetic stirrer and a nitrogeninlet was charged with the residue prepared in Step C above (26 g, 75.5mmol) in EtOH (600 mL). The reaction mixture was cooled in an ice bathand a solution of cyanogen bromide in MeCN (5M, 15.1 mL, 75.5 mmol) wasadded in one portion. The reaction mixture was warmed to roomtemperature, stirred for 4 days and then brought to reflux for 3 h. Thereaction mixture was cooled to room temperature, poured into water (1.2L), basified with 3M aqueous sodium hydroxide, and stirred in anice-water bath for 2 h. The resulting solid was collected by filtration,washed with 1:9 water:EtOH (250 mL), and dried to yield a solid.

mp 199-205° C., decomp.

Mass spectrum (Electrospray, positive mode): m/z=368/370 (M⁺)

Elemental analysis: (C₁₅H₂₁BrN₄O₂):

Calc'd: % C, 48.79; % H, 5.73; % N, 15.17; % Br, 21.64.

Found: % C, 49.63; % H, 5.81; % N, 15.30; % Br, 21.22.

Karl-Fisher: 0.14% (w/w) water

HPLC: R_(t)=7.967 min; Agilent Eclipse XDB-C8, 5 μm, 4.6×150 mm.Gradient: A=water (0.1% TFA), B=MeCN (0.1% TFA)@1.0 mL/min. Initial:A:B, 90:10. t=0.00-0.50 min (A:B, 90:10), t=0.50-11.50 min (A:B, 5:95),t=11.50-12.50 min (A:B, 5:95)

Step E

To a reaction vessel containing the solid prepared in Step D above (66mg, 0.18 mmol) was added 50% TFA:DCM (1.4 mL). The reaction mixture wasstirred at 40° C. for 2 h and then was concentrated in vacuo to yield aresidue, which was taken into the next step without furtherpurification.

Step F

To the residue isolated in Step E was added chloroform (0.5 mL), TEA(138 gL, 0.99 mmol), and cyclopentanecarbonyl chloride (24 mg, 0.18mmol) in chloroform (0.2 mL). The mixture was stirred at roomtemperature overnight and then was concentrated in vacua. To the residuewas added methanol (0.2 mL) and the solution was concentrated to furnisha residue.

Step G

To a reaction vessel containing the residue prepared in Step F above wasadded o-tolylboronic acid (37 mg, 0.27 mmol) in EtOH (1 mL), K₂CO₃ (50mg, 0.36 mmol) in water (0.2 mL), and[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (7 mg,0.008 mmol). The reaction mixture was irradiated (microwave) at 120° C.for 6 min and then was concentrated in vacua. The residue was taken upin 1% TEA:EtOAc (0.8 mL) and water (0.35 mL). The solution was absorbedonto diatomaceous earth and eluted with 1% TEA:EtOAc. The eluate wasconcentrated to a residue and then was purified by reverse-phasechromatography to yield the title compound, cyclopentanecarboxylic acid[2-(2-amino-6-o-tolyl-4H-quinazolin-3-yl)-ethyl]-amide as atrifluoroacetate salt as an oil.

MS m/z (MH⁺) calcd 377.23, found 377.4

EXAMPLE 253-[2-Amino-6-(2-methoxy-phenyl)-4H-quinazolin-3-ylmethyl]-N-cyclohexyl-N-methyl-benzamide(Compound #167)

Step A

To a flask containing 3-cyanobenzoic acid (10 g, 0.068 mol) in DCM (300mL) was added DIEA (47 mL, 0.27 mol) and N-methylcyclohexylamine (13.3mL, 0.1 mol) with stirring. The resulting solution was cooled toapproximately 0° C., and then 2-chloro-1,3-dimethylimidazolium chloride(23 g, 0.14 mol) was added with stirring. After 5 minutes, the coolingbath was removed and the solution was warmed to room temperature over 4h. The reaction mixture was quenched with 100 mL of water, transferredto a separatory funnel, shaken, and the layers were separated. Theaqueous layer was extracted with DCM (2×100 mL) and the combinedorganics were dried over Na₂SO₄, filtered, concentrated to a residue,and placed under vacuum (˜1 mmHg) for 1 h.

Step B

The residue prepared in Step A above was transferred to a Parr bottlewith EtOH (250 mL) and then was degassed and blanked with nitrogenbefore 12N aqueous HCl (28 mL, 0.34 mol) and 10% Pd/C (1.6 g) slurriedin water were added. The resulting slurry was exposed to 50 psi of H₂for 14 h at room temperature using standard Parr techniques and thendegassed with nitrogen for 5 minutes and filtered through a pad ofCelite®. The resulting solution was concentrated to the aqueous layerand transferred to a separatory funnel with water (100 mL) and DCM (50mL). The layers were separated and the aqueous layer was extracted withDCM (2×25 mL). The combined organic layers were extracted with 0.5N HCl(25 mL), and the layers were separated. The combined aqueous layers wereadjusted to pH>9 with 3N NaOH and extracted with DCM (5×50 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, concentratedto a residue, and placed under vacuum (˜1 mmHg) for 1 day.

MS m/z (MH⁺) calcd 247.2, found 247.3

Step C

To a round-bottomed flask containing the residue prepared in Step Babove (6.7 g, 0.032 mol) in DCE (175 mL) was added5-bromo-2-nitrobenzaldehyde (7.4 g, 0.032 mol). After stirring at roomtemperature for 30 min, NaBH(OAc)₃ (13.7 g, 0.065 mol) was added, andthe reaction mixture was stirred at room temperature for 18 h. Thereaction mixture was quenched with 1 N NaOH (100 mL). The layers wereseparated, and the aqueous layer was extracted with DCM (3×25 mL). Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated in vacuo to constant weight to yield a residue which wasused in the following step without further purification.

MS m/z (MH⁺) calcd 460.1, found 460.4

Step D

To a solution of the residue prepared in Step C above (27 mg, 0.059mmol) in EtOH (0.5 mL) was added K₂CO₃ (12.3 mg, 0.089 mmol) in water(0.025 mL), 2-methoxyphenylboronic acid (13.5 mg, 0.089 mmol) andbis(diphenyl-phosphino)ferrocene dichloropalladium (4.9 mg, 0.006 mmol).The reaction mixture was irradiated (sw) at 100° C. for 10 min. Aftercooling to room temperature, the solution was used directly in thefollowing step.

MS m/z (MH⁺) calcd 488.3, found 488.6

Step E

To the solution prepared in Step D above was added SnCl₂ (56 mg, 0.30mmol) in EtOH (0.2 mL), and the resulting solution was stirred at roomtemperature for 36 h. The reaction mixture was quenched with water (0.1mL) and TEA (0.2 mL), stirred for 5 minutes, and concentrated to aresidue. The residue was suspended in 1% TEA in EtOAc and loaded on a 2g silica SPE cartridge and then eluted with 15 ml of 1% TEA in EtOAc.The eluent was concentrated in vacuo to yield a residue which was useddirectly in the next step without further purification.

MS m/z (MH⁺) calcd 458.3, found 458.7

Step F

The residue prepared in Step E above was dissolved in EtOH (0.75 mL),and cyanogen bromide (0.047 mL, 0.24 mmol, 5M in MeCN) was added. Theresulting solution was stirred for 18 h at room temperature. Thereaction mixture was quenched with 3M NaOH (0.1 mL), stirred for 5minutes, and concentrated in vacuo. The residue was suspended inDCM:water (1 mL:0.1 mL), and the inorganic materials were removed by SLE(solid liquid extraction) cartridge. After concentration, the resultingresidue was purified by preparative RP-HPLC to yield the title compound,3-(2-amino-6-phenoxy-4H-quinazolin-3-ylmethyl)-N-cyclohexyl,N-methyl-benzamide as an oil.

MS m/z (MH⁺) calcd 483.3, found 483.6

EXAMPLE 263-(2-Amino-6-phenoxy-4H-quinazolin-3-ylmethyl)-N-cyclohexyl-N-methyl-benzamide(Compound #62)

Step A

To a solution of 3-(tert-butoxycarbonylamino-methyl)-benzoic acid (1.00g, 3.98 mmol) in 21 mL of DMF was added 1,1′-carbonyldiimidazole (0.645g, 3.98 mmol). After 1.5 h of stirring at room temperature,N-methylcyclohexylamine (0.98 mL, 7.50 mmol) was added. After another 2h of stirring, 50 mL of water was added to the reaction mixture. Thereaction mixture was then extracted with diethyl ether. The diethylether extracts were combined, washed with water (2×) and brine (2×),dried over Na₂SO₄. After filtration, the diethyl ether solution wasconcentrated in vacuo to yield an oil.

MS m/z (MH⁺)=347

Step B

To a solution of the oil prepared in Step A above (0.402 g, 1.17 mmol)in CH₂Cl₂ (40 mL), was added TFA (4.0 mL). The reaction mixture wasstirred overnight, and then 3N NaOH solution (35-40 mL) was added withvigorous stirring. The organic layer was separated, dried over Na₂SO₄,filtered, and evaporated to yield an oil.

MS m/z (MH⁺)=247

Step C

A solution of the oil prepared in Step B above (0.051 g, 0.21 mmol) and2-nitro-5-phenoxybenzaldehyde (0.051 g, 0.21 mmol) in 1 mL of DCE wasstirred for 10 minutes. Then NaBH(OAc)₃ (0.062 g, 0.29 mmol) was added.The reaction mixture was stirred overnight at room temperature, and then3N NaOH solution was added with vigorous stirring. The organic layer wasseparated, dried over Na₂SO₄, filtered, and evaporated to yield a thickoil.

MS m/z (MH⁺)=474

Step D

A mixture of the oil prepared in Step C above (0.049 g, 0.10 mmol) andtin(II) chloride dihydrate (0.124 g, 0.55 mmol) in 0.4 mL of EtOH wasrefluxed for 1 hour. The reaction mixture was cooled and saturatedNaHCO₃ solution and EtOAc were added with thorough mixing. The organiclayer was separated, dried over Na2SO₄, filtered, and evaporated toyield a glassy solid.

MS m/z (MH⁺)=444

Step E

A solution of the glassy solid prepared in Step D above (0.037 g, 0.084mmol) and cyanogen bromide (0.013 g, 0.12 mmol) in 2 mL of EtOH wasrefluxed for 2 h. The reaction mixture was cooled and evaporated. Theresidue was triturated with diethyl ether and filtered to yield thetitle compound as a brown solid.

MS m/z (MH⁺)=468

EXAMPLE 274-{[4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4-(S)-cyclohexyl-butyryl]-methyl-amino}-cyclohexanecarboxylicacid (Compound #714)

Step A

A solution of 4-cyclohexanonecarboxylic acid ethyl ester (6 g, 35 mmol),methylamine·HCl salt (2.4 g, 35 mmol), triethylamine (0.15 mL, 3 mol%)and wet 5% Pd/C (0.18 g, 3% wt) in MeOH (100 mL) was placed into ahydrogenation bottle. The reaction mixture was subjected tohydrogenation at 60 psi and 50° C. overnight. The catalyst was removedby filtration, and the MeOH was evaporated. The residue was stirred inEtOAc: hexane (1:1) for 30 min. The suspension was filtered, and a whitesolid was collected as its HCl salt.

MS m/z (MH⁺)=186.2

Step B

To an ice cooled solution of4-tert-butoxycarbonylamino-4-(S)-cyclohexyl-butyric acid (3.8 g, 0.014mol; prepared as in Example 22, Steps A-E) in CH₂Cl₂ (200 mL), was addedthe amine (3.2 g, 0.0144 mol) prepared in Step A, HOBT (2.4 g, 0.017mol) and TEA (5.5 mL, 0.042 mol) followed by addition of1,3-dimethylamino propyl-3-ethylcarbodiimide (EDC) (3.3 g, 0.017 mol).The reaction mixture was allowed to warm to room temperature and wasstirred overnight. EtOAc (300 mL) was then added to the reactionmixture. The resulting mixture was washed with citric acid solution,aqueous NaHCO₃, and brine. The organic layer was collected, dried(MgSO₄) and evaporated to yield an oil. The crude oil was used in thenext step without further purification.

MS m/z (MH⁺)=453.1

Step C

A solution of the material (6 g, 13 mmol) isolated in Step B in 20%TFA-CH₂Cl₂ (100 mL) was stirred at room temperature for 3 h. The solventand most of TFA was evaporated, and EtOAc (200 mL) was added to theresidue. The EtOAc extract was washed with aqueous NaHCO₃ solution andbrine and then dried (MgSO₄) and evaporated to yield a light brown oil.

MS m/z (MH⁺)=353.3

Step D

To a solution of the oil (4.8 g,13.6 mmol) from Step C in DCE (200 mL)was added 2-nitro-5-phenoxybenzaldehyde (3.9 g, 16 mmol), acetic acid(0.9 mL), and NaBH(OAc)₃ (4.7 g, 20 mmol). The reaction mixture wasstirred overnight, and then extracted with EtOAc (2×200 mL). The organiclayers were combined, dried (Mg₂SO₄), and evaporated. Purification on asilica gel column (1:1 heptane:EtOAc) yielded an oil.

MS m/z (MH⁺)=580.4

Step E

To a solution of the oil (2.9 g, 5 mmol) isolated in Step D in MeOH (100mL) was added 10% Pd/C (0.29 g) on activated carbon under N₂. Thereaction mixture was subjected to hydrogenation at 5 psi for 2 h. Thecatalyst was removed by filtration, and then the MeOH was evaporated.Purification on flash silica gel (100% EtOAc) yielded a solid.

MS m/z (MH⁺)=550.7

Step F

A solution of the solid isolated (2.2 g, 4.1 mmol) in Step E and BrCN(3M in CH₂Cl₂, 1.4 mL, 4.3 mmol) in EtOH (50 mL) was stirred at roomtemperature overnight. The EtOH was evaporated to yield a residue whichwas purified on silica gel (10% 1 M NH₃ in MeOH:CH₂Cl₂) to yield asolid.

MS m/z (MH⁺)=575.3

Step G

A solution of the solid (1.75 g, 3 mmol) isolated in Step F in MeOH (20mL) and 1 N NaOH (3.2 mL, 3.2 mmol) was stirred at room temperature overthe weekend. Mass spectral analysis indicated that starting material wasstill left so additional 1 N NaOH (3 mL) was added. The solution wasstirred at room temperature for 6 h. Citric acid (1.4 g, 6.6 mmol) wasadded, and the reaction mixture was stirred for 1 h. The solvent wasevaporated to yield crude product. 1.2 g of the crude product waspurified by HPLC to yield title compound,4-{[4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4-cyclohexyl-butyryl]-methyl-amino)-cyclohexanecarboxylicacid, as a white solid.

MS m/z (MH⁺)=547.4

¹H NMR (300 MHz, CD₃OD): δ0.91-1.25 (m, 4H), 1.51-1.76 (m, 10H),2.02-2.21 (m, 8H), 2.57-2.76 (m, 1H), 2.81 (s, 3H), 3.5 (m, 0.4×1H),3.73 (s, 2H), 4.15 (m, 2H), 4.4 (m, 0.6×1H), 6.72 (s, 1H), 6.94 (d,J=7.78 Hz, 2H), 7.10 (t, J=7.44 Hz, 1H), 7.2-7.36 (m, 4H).

EXAMPLE 28 (S)-enantiomer of4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4,N-dicyclohexyl-N-(2-hydroxy-ethyl)-butyramide(Compound #736)

Step A

To an ice cooled solution of Boc-D-cyclohexylglycine (10 g, 39 mmol),N,O-dimethylhydroxyamine·HCl salt (4.6 g, 46 mmol) and HOBT (7 g, 51mmol) in CH₂Cl₂ (200 mL), TEA (11 mL) was added followed by addition ofEDC (10 g, 51 mmol). The reaction mixture was allowed to warm to roomtemperature and was then stirred overnight. EtOAc (300 mL) was added.The reaction mixture was then washed with citric acid solution, NaHCO₃solution, and NaCl solution. The organic layer was collected, dried withMgSO₄ and evaporated to yield a colorless oil. The crude product wasused without further purification.

MH⁺301.2

Step B

To an ice cooled solution of the oil isolated in Step A above (12.3 g,40 mmol) in THF (100 mL) was slowly added LAH (1M solution in THF, 45mL) so as to keep the reaction temperature below about 5° C. The icebath was removed, and the reaction mixture was stirred at roomtemperature for 20 min. A solution of NaHSO₄ (7.3 g) in water (10 mL)was slowly added to quench the reaction. The reaction mixture was thenfiltered through Celite®. EtOAc (300 mL) was added to the filtrate, andthe organic layer was washed with NaCl solution, dried with MgSO₄ andevaporated to yield an oil. The crude product was used without furtherpurification.

MH⁺242.2

Step C

To an ice cooled solution of trimethyl phosphonoacetate (19 mL, 0.11mol) in THF (200 mL) was added 60% NaH (3.1 g, 0.08 mol) in portions.The ice bath was removed, and the reaction mixture was stirred at roomtemperature for 30 min. The reaction mixture was cooled to 0° C. againbefore a solution of the oil isolated in Step B (9 g, 37 mmol) in THF(200 mL) was added. The reaction mixture was stirred at room temperaturefor another 20 min. Water (100 mL) was added, and most of the THF wasevaporated. The product was extracted into EtOAc (400 mL), and theorganic layer was washed with NaCl solution and dried with MgSO₄. Columnchromatography (1:1 heptane:EtOAc) yielded a white solid.

¹H NMR (300 MHz, CDCl₃): δ1.1-1.3 (m, 7H), 1.44 (s, 9H), 1.6-1.8 (m,5H), 3.73 (s, 3H), 4.17 (m, 0.6xlH), 4.58 (m, 0.4×1H), 5.9 (dd, J=1.4Hz, J=15.6 Hz, 1H), 6.88 (dd, J=5.6 Hz, J=15.6 Hz, 1H).

Step D

To a solution of the white solid isolated in Step C (9 g, 30 mmol) inMeOH (100 mL) was added 10% Pd on activated carbon (1 g) under N₂. Thereaction mixture was hydrogenated at 20 psi for 4 hours. The catalystwas removed by filtration, and the MeOH was evaporated to yield a whitesolid.

¹H NMR (300 MHz, CDCl₃): δ0.9-1.3 (m, 7H), 1.43 (s, 9H), 1.5-1.8(m, 6H),2.37 (t, J=7.52 Hz, 2H), 3.4 (m, 1H), 3.67 (s, 3H), 4.29 (m, 1H).

Step E

To a solution of the solid isolated in Step D (9 9) in MeOH (100 mL) wasadded 1 N NaOH (31 mL). The reaction mixture was stirred at roomtemperature overnight. Citric acid (7 g) was added, and the MeOH wasremoved in vacuo. The product was extracted into EtOAc (300 mL). Theorganic layer was washed with NaCl solution and then dried with MgSO₄ toyield a white solid.

MH⁻284.1

Step F

To an ice cooled solution of N-cyclohexylethanolamine (0.55 g, 3.9 mmol)in CH₂Cl₂ (200 mL), the solid isolated in Step E (1.0 g, 3.5 mmol), HOBT(0.62 g, 4.5 mmol), TEA (1.0 mL) were added followed by EDC (0.87 g, 4.5mmol). The reaction mixture was allowed to warm to room temperature andwas stirred overnight. EtOAc (300 mL) was added to the reaction mixture.The reaction mixture was washed with citric acid solution, NaHCO₃solution, and NaCl solution. The organic layer was collected, dried withMgSO₄, and evaporated to yield an oil. The crude oil product was usedwithout. further purification.

MH⁺411.4

Step G

A solution of the oil isolated in Step F (1.5 g, 3.6 mmol) in 20%TFA:CH₂Cl₂ (60 mL) was stirred at room temperature for one hour. Thesolvent and most of the TFA was evaporated, and EtOAc (200 mL) wasadded. The reaction mixture was washed with NaHCO₃ solution and NaClsolution. The organic layer was dried with MgSO₄ and evaporated to yielda light brown oil.

MH⁺311.0

Step H

To a solution of the oil isolated in Step G (0.4 g, 1.3 mmol) and2-nitro-5-phenoxybenzaldehyde (0.31 g, 1.3 mmol) in 1,2-dichloroethane(50 mL), NaBH(OAc)₃ (0.37 g, 2.0 mmol) was added. The reaction mixturewas stirred at room temperature overnight. A solution of 1 N NaOH wasadded, and the reaction mixture was extracted with EtOAc (2×200 mL). Theorganic layer was dried with MgSO₄ and evaporated. Purification bycolumn chromatography (1:1 heptane/EtOAc) yielded an oil.

MH⁺538.4

Step I

To a solution of the oil isolated in Step H (0.07 gm, 0.13 mmol) in MeOH(10 mL) was added a catalytic amount of 10% palladium on activatedcarbon under N₂. The reaction mixture was subjected to hydrogenation at5 psi for one hour. The catalyst was filtered out, and the MeOH wasevaporated to yield a residue. Purification by preparative TLC (100%EtOAc) yielded an oil.

MH⁺508.3

Step J

To a solution of the oil isolated in Step 1 (0.03 g, 0.06 mmol), BrCN(3M in CH₂Cl₂, 0.02 mL) in EtOH (5 mL) was added. The reaction mixturewas stirred at room temperature overnight. The EtOH was evaporated toyield an oil which was stirred in diethyl ether (50 mL) for 30 min. Asolid formed, and was collected by filtration. The product was isolatedas a solid, as its corresponding HBr salt.

MH⁺533.3

¹H NMR (300 MHz, CDCl₃): δ0.9-1.9 (m, 22H), 2.0-2.2 (m, 1H), 2.3-2.5 (m,2H), 3.3-3.8 (m, 5H), 4.1-4.3 (m, 3H), 6.72 (s, 1H), 6.91 (d, J=8.54 Hz,2H), 7.15 (d, J=8.25 MHz, 1H), 7.2 (m, 2H) 7.34 (t, J=7.8 Hz, 2H).

EXAMPLE 29 S-enantiomer of4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-N-cyclohexyl-4-(1,4-dioxa-spiror4.5]dec-8-yl)-N-methyl-butyramide(Compound #730)

Step A

A solution of N-benzyloxycarbonyl-α-phosphonoglycine trimethyl ester (5g, 15 mmol) and DBU (2.3 mL, 15 mmol) in THF (50 mL) was stirred at roomtemperature for 10 min before adding dropwise a solution of1,4-cyclohexanedione mono-ethylene ketal (2.4 g, 15 mmol) in THF (20mL). The reaction mixture was stirred at room temperature overnightbefore adding 5% HCl (50 mL). The reaction mixture was extracted withEtOAc (3×100 mL). The combined organic layers were washed with aqueousNaCl solution, dried with MgSO₄, and evaporated. Column chromatography(1:1 hexane:EtOAc) yielded a light yellow oil which turned into a solidupon standing.

MH⁺362.1

Step B

A solution of the solid isolated in Step B (3.2 g, 8.8 mmol) andR,R-(+)-BPE (1,2-bis(phospholano)ethane)-Rh catalyst (0.03 g) in MeOH(60 mL) was placed into a Parr high pressure reactor and subjected tohydrogenation under 410 psi for three days. The MeOH was removed, andcolumn chromatography (1:1 hexane:EtOAc) yielded an oil which turned toa solid overnight.

MH⁺364.2

Step C

To a solution of the solid isolated in Step B (2.8 g, 8 mmol) in MeOH(50 mL) was added 1 N NaOH (8 mL, 8 mmol). The solution was stirred atroom temperature overnight. Citric acid (3.1 g, 17 mmol) was added, andthe reaction mixture was stirred another 10 min. The MeOH wasevaporated, and the resulting solution was extracted with EtOAc (200mL). The organic layer was washed by aqueous NaHCO₃ solution and aqueousNaCl solution and then was dried with MgSO₄. Evaporation yielded an oil,which turned to a solid upon standing.

MH⁻348.1

Step D

To an ice-cooled solution of the solid isolated in Step C (2.8 g, 8mmol), N,O-dimethylhydroxylamine·HCl salt (0.86 μm, 8.8 mmol) and HOBT(1.5 g, 11 mmol) in CH₂Cl₂ (100 mL) was added TEA (3 mL) followed byaddition of EDC (2.2 g, 11 mmol). The reaction mixture was allowed towarm to room temperature and was stirred overnight. EtOAc (100 mL) wasadded to the reaction mixture which was then washed with citric acidsolution, NaHCO₃ solution, and NaCl solution. The organic layer was thendried with MgSO₄ and evaporated to yield an oil. The crude oil productwas used without further purification.

MH⁺393.3

Step E

To an ice cooled solution of the oil isolated in Step D (2.8 g, 7.1mmol) in THF (50 mL) was slowly added LAH (1 M solution in THF, 7.2 mL)in order to keep the reaction temperature below 5° C. The ice bath wasremoved, and the reaction mixture was stirred at room temperature for 20min. A solution of NaHSO₄ (1.1 g) in water (3 mL) was slowly added toquench the reaction. The reaction mixture was then filtered thrbughCelite®. EtOAc (100 mL) was added, and the organic layer was washed withNaCl solution, dried with MgSO₄, and evaporated to yield an oil. Thecrude oil product was used without further purification.

MH⁺334.1

Step F

To an ice cooled solution of trimethyl phosphonoacetate (3.5 mL, 21mmol) in THF (200 mL) was added 60% NaH (0.6 g, 14 mmol) in portions.The ice bath was removed and the reaction mixture was stirred at roomtemperature for 30 min. The reaction mixture was cooled to 0° C. againbefore a solution of the oil isolated in Step E (2.3 g, 7 mmol) in THF(100 mL) was added. The ice bath was removed, and the reaction mixturewas stirred at room temperature for another 20 min. Water (50 mL) wasadded, and most of the THF was evaporated. The aqueous solution wasextracted with EtOAc (200 mL), and the organic layer was washed withNaCl solution and dried with MgSO₄. Purification by columnchromatography (1:1 heptane/EtOAc) yielded a white solid.

MH⁺390.2

Step G

A solution of the white solid isolated in Step F (1.7 g, 4.4 mmol), 10%Pd/C (1.1 9), Boc anhydride (1.0 g, 4.4 mmol), 1,4-cyclohexadiene (3 mL,44 mmol) in EtOH (50 mL) was stirred at room temperature for 3 hours.The catalyst was removed by filtration, and EtOH was evaporated to yielda colorless oil.

MH⁺358.2

Step H

The oil (1.1 g) isolated in Step G was dissolved in MeOH (20 mL) beforeadding 1 N NaOH (3.0 mL). The reaction mixture was stirred at roomtemperature overnight and then was acidified with citric acid (1.2 g).The MeOH was removed by vacuum. The product was extracted into EtOAc(100 mL). The organic layer was washed with NaCl solution, dried withMgSO₄, and. concentrated to yield a yellow oil.

MH⁻342.1

Step I

To an ice cooled solution of the oil isolated in Step H (0.82 g, 2.4mmol), N-methylcyclohexylamine (0.35 mL, 2.7 mmol), HOBT (0.42 g, 3.1mmol) in CH₂Cl₂ (50 mL), was added TEA (0.7 mL) followed by addition ofEDC (0.62 g, 3.1 mmol). The reaction mixture was allowed to warm to roomtemperature and was stirred overnight. EtOAc (100 mL) was added. Thereaction solution was washed with citric acid solution, NaHCO₃ solution,and NaCl solution. The organic layer was separated, dried with MgSO₄,and evaporated to yield a brown oil which was used withoutfurther-purification.

MH⁺439.3, MH⁺339.1 (M-Boc)

Step J

A solution of the oil isolated in Step I (1.0 g, 2.3 mmol) in 20%TFA-CH₂Cl₂ (60 mL) was stirred at room temperature for one hour. Thesolvent was evaporated along with most of the TFA, and EtOAc (100 mL)was added. The reaction mixture was washed with NaHCO₃ solution and NaClsolution. The organic layer was dried with MgSO₄ and evaporated to yielda brown oil.

MH⁺339.0

Step K

To a solution of the oil isolated in Step J (0.4 g, 1.1 mmol) and2-nitro-5-phenoxy-benzaldehyde (0.3 g, 1.2 mmol) in 1,2-dichloroethane(20 mL), was added NaBH(OAc)₃ (0.44 g, 2.1 mmol). The reaction mixturewas stirred at room temperature overnight. A solution of 1 N NaOH wasthen added. The reaction mixture was extracted with EtOAc (100 mL). Theorganic layer was dried with MgSO₄ and evaporated. Column chromatography(1:1 heptane:EtOAc) yielded an oil.

MH⁺566.5

Step L

To a solution of the oil isolated in Step K in MeOH (10 mL) was added10% Pd/C (0.02 g) under N₂. The reaction mixture was subjected tohydrogenation at 5 psi for one hour. The catalyst was filtered out, andthe MeOH was evaporated to yield a residue. Purification by preparativeTLC (100% EtOAc) yielded an oil.

MH⁺536.4

Step M

To a solution of the oil isolated in Step L (0.06 g, 0.1 mmol) in EtOH(5 mL) was added BrCN (3M in CH₂Cl₂, 0.04 mL). The reaction mixture wasstirred at room temperature overnight. The EtOH was evaporated to yieldan oil that was stirred in diethyl ether (50 mL) for 30 min. Aprecipitate formed, and the suspension was filtered to yield the titlecompound as a solid, as its HBr salt.

MH⁺561.3

¹H NMR (300 MHz, CD₃OD): δ0.9-1.8 (m, 22H), 2.3-2.5(m, 6H), 3.21(s, 3H),3.81 (s, 2H), 6.86 (m, 4H), 7.03 (m, 2H), 7.24 (m, 2H)

EXAMPLE 30 (S)-enantiomer of4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-N-cyclohexyl-N-methyl-4-(4-oxo-cyclohexyl)-butyramide(Comp ound #732)

A solution of the compound prepared as in Example 29 (0.06 g, 0.1 mmol)in 1 N HCl (1 mL) and THF (1 mL) was stirred at room temperatureovernight. The THF was evaporated, and the crude product was dissolvedin a small amount of MeOH. Purification by preparative HPLC yielded thetitle compound as a solid, as its corresponding TFA salt.

MH⁺517.2

¹H NMR (300 MHz, CDCl₃): δ1.2-1.8 (m, 20H), 2.1-2.4 (m, 4H), 2.8 (d,J=15 Hz, 3H), 3.44 (m, 0.4×1H), 4.23 (s, 2H), 4.4 (m, 0.6×1H), 6.72 (s,1H), 6.95 (d, J 7.61Hz, 2H), 7.12 (d,1H), 7.27-7.34 (m, 4H).

EXAMPLE 314-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-N-cyclohexyl-4-(4-hydroxy-cyclohexyl)-N-methyl-butyramide(Compound #632)

Step A

A solution of the compound prepared as in Example 29, Step A (4.0 g, 11mmol), 10% Pd/C (4 g), Boc anhydride (3.6 g, 16 mmol), and1,4-cyclohexadiene (10.4 mL, 0.1 mol) in EtOH (60 mL) was stirred atroom temperature for 2 hours. The catalyst was removed by filtration,and the EtOH was evaporated to yield a residue. The residue was purifiedby column chromatography (1:1 hexane:EtOAc) to yield a colorless oil.

MH⁺330.0, MH⁺230.2 (M-Boc)

Step B

To a solution of the oil isolated in Step A (1 g, 3 mmol) in MeOH (20mL) was added 1 N NaOH (5 mL, 5mmol). The reaction mixture was stirredat room temperature overnight. The MeOH was evaporated, and the productwas extracted into EtOAc (200 mL). The organic layer was washed withdilute HCl solution, NaHCO₃ solution, aqueous NaCl solution, dried withMgSO₄, and evaporated to yield an oil.

MH⁻314

Step C

To an ice-cooled solution of the oil isolated in Step B (1.0 g, 3 mmol),N,O-dimethylhydroxyamine·HCl salt (0.6 g, 6 mmol) and HOBT (0.78 g, 6mmol) in CH₂Cl₂ (50 mL), was added TEA (1.3 mL) followed by addition ofEDC (1.2 g, 6 mmol). The reaction mixture was allowed to warm to roomtemperature and was then stirred overnight. EtOAc (100 mL) was added,and the reaction mixture was washed with citric acid solution, NaHCO₃solution, and NaCl solution. The organic layer was dried with MgSO₄ andevaporated to yield an oil. The crude oil product was used withoutfurther purification.

MH⁺359.1, MH⁺259.1 (M-Boc)

Step D

To an ice cooled solution of the oil isolated in Step C (1.2 g, 3.3mmol) in THF (50 mL) was slowly added LAH (1 M solution in THF, 4 mL)while keeping the temperature below 5° C. The ice bath was removed, andthe reaction mixture was stirred at room temperature for 20 min. Asolution of NaHSO₄ (0.9 g) in water (3 mL) was slowly added to quenchthe reaction. The reaction mixture was then filtered through Celite®.EtOAc (100 mL) was added and the organic layer was washed with NaClsolution, dried with MgSO₄ and evaporated to yield an oil. The crudeproduct was used without further purification.

MH⁺300.1, MH⁺200.1 (M-Boc)

Step E

To an ice cooled solution of trimethyl phosphonoacetate (5.5 mL, 33mmol) in THF (200 mL) was added 60% NaH (1.4 g, 22 mmol) in portions.The ice bath was removed, and the reaction mixture was stirred at roomtemperature for 30 min. The reaction mixture was cooled to 0° C. againbefore a solution of the oil isolated in Step D (3.4 g, 11 mmol) in THF(100 mL) was added. The cooling bath was removed, and the reactionmixture was stirred at room temperature for another 20 min. Water (50mL) was then added, and most of the THF was evaporated. The product wasextracted into EtOAc (200 mL), and the organic layer was washed withNaCl solution, dried with MgSO₄, and evaporated. Purification by columnchromatography (1:1 heptane:EtOAc) yielded a white solid.

¹H NMR (300 MHz, CDCl₃): δ1.1-1.8 (m, 12H), 3.73 (s, 3H), 3.93 (m, 1H),4.25 (m, 0.6×1H), 4.68 (m, 0.4×1H), 5.9 (dd, J=1.6 Hz, J=14 Hz, 1H),6.85 (dd, J=.5.1Hz, J=15 Hz, 1H).

Step F

To a solution of the white solid isolated in Step E (2.0 g) in MeOH (50mL) was added 10% Pd/C (0.2 g) under N₂, and the reaction mixture washydrogenated at 30 psi for three hours. The catalyst was removed byfiltration, and the MeOH was evaporated to yield an oil.

MH⁺358.2, MH⁺258.1 (M-Boc)

Step G

To a solution of the oil isolated in Step F (1.15 g, 3.2 mmol) in MeOH(15 mL) was added 1 N NaOH (5 mL, 5 mmol). The reaction mixture wasstirred at room temperature overnight. The MeOH was evaporated, and theproduct was extracted into EtOAc (100 mL). The organic layer was washedwith dilute HCl solution, NaHCO₃ solution, and aqueous NaCl solution,dried with MgSO₄, and evaporated to yield a colorless oil.

MH⁺344.1, MH⁻342.0

Step H

To an ice cooled solution of N-methylcyclohexylamine (0.4 mL, 3.0 mmol),the oil isolated in Step G (0.95 g, 2.8 mmol), and HOBT (0.41 g, 3.0mmol) in CH₂Cl₂ (50 mL), was added TEA (0.77 mL) followed by addition ofEDC (0.58 g, 3.0 mmol). The reaction mixture was allowed to warm to roomtemperature and then was stirred overnight. EtOAc (100 mL) was added.The organic solution was washed with citric acid solution, NaHCO₃solution, and NaCl solution. The organic layer was separated and driedwith MgSO₄ and then was evaporated to yield a brown oil. The crude oilproduct was used without further purification.

MH⁺439.3, MH⁺339.2 (M-Boc)

Step I

A solution of the oil isolated in Step H (1.1 g, 2.5 mmol) in 20%TFA:CH₂Cl₂ (50 mL) was stirred at room temperature for one hour. Thesolvent and most of TFA was evaporated, and EtOAc (100 mL) was added.The EtOAc solution was washed with NaHCO₃ solution and NaCl solution.The organic layer was dried with MgSO₄ and evaporated to yield a brownoil.

MH⁺339.2

Step J

To a solution of the oil isolated in Step I (0.74 g, 2.1 mmol),2-nitro-5-phenoxybenzaldehyde (0.55 g, 2.2 mmol), and HOAc (0.15 mL) in1,2-dichloroethane (20 mL) was added NaBH₃CN (0.20 g, 3.2 mmol). Thereaction mixture was stirred at room temperature overnight. The reactionmixture was poured into 1 N NaOH (10 mL) and extracted with EtOAc (100mL). The organic layer was dried with MgSO₄ and evaporated. Purificationby column chromatography (1:1 heptane:EtOAc) yielded a colorless oil.

MH⁺566.2

Step K

A solution of the oil isolated in Step J (0.41 g, 0.72 mmol) in 1 N HCl(2 mL) in THF (5 mL) was stirred at room temperature overnight. EtOAc(50 mL) and NaHCO₃ solution (20 mL) were added to the reaction mixture.The organic layer was separated, dried with MgSO₄ and evaporated toyield a colorless oil.

MH⁺522.3

Step L

To a solution of the oil isolated in Step K (0.14 g, 0.27 mmol) in MeOH(5 mL) was added NaBH₄ (0.01 g, 0.27 mmol). The reaction mixture wasstirred at room temperature for one hour. The MeOH was evaporated, andEtOAc (50 mL) was added to the residue. The EtOAc solution was thenwashed with NaCl solution, dried with MgSO₄, and evaporated to yield acolorless oil.

MH⁺524.6

Step M

To a solution of the oil isolated in Step L (0.14 g) in MeOH (10 mL),10% Pd/C (0.01 g) was added under N₂. The mixture was hydrogenated at 5psi for one hour. The catalyst was removed by filtration, and the MeOHwas evaporated to yield an oil.

MH⁺494.3

Step N

The oil (0.1 g) isolated in Step M was re-dissolved in EtOH (5 mL). BrCN(3M in CH₂Cl₂, 0.02 mL) was added, and the reaction mixture was stirredat room temperature overnight. The EtOH was evaporated to yield an oilwhich was stirred in diethyl ether (50 mL) for 30 min. The resultingsolid was collected and recrystallized from ethyl ether/ethyl acetate(3:1) to yield the title compound as an off-white solid, as its HBrsalt.

MH⁺519.5

¹H NMR (300 MHz, CDCl₃): δ0.9-2.1 (m, 22H), 2.6-2.7 (m, 1H), 2.84 (s,0.63×3H), 3.3-3.5 (m, 2H), 4.19 (d, J=5.7 Hz, 2H), 6.72 (s, 1H), 6.98(d, J=7.7 Hz, 2H), 7.12 (m, 1H), 7.2-7.3 (m, 3H), 8.18 (s, 1H)

EXAMPLE 32 (S)-enantiomer of4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-N-cyclohexyl-N-methyl-4-(tetrahydro-pyran-4-yl)-butyramide(Compound #709)

Step A

To a solution of N-benzyloxycarbonyl-α-phosphonoglycine trimethyl ester(6.6 g, 20 mmol) and 1,1,3,3-tetramethylguanidine (3.3 mL, 27 mmole) inTHF (50 mL) was added dropwise a solution of tetrahydro-4H-pyran-4-one(2 g, 20 mmol) in THF (30 mL). The reaction mixture was stirred at roomtemperature overnight, and then 5% HCl (50 mL) was added. The reactionmixture was then extracted with EtOAc (200 mL and then 100 mL portions).The combined organic layers were washed with aqueous NaCl solution,dried with MgSO₄, and evaporated. The residue was recrystallized twicefrom EtOAc and hexane to yield a white solid.

MH⁺306.0

Step B

A solution of the solid isolated in Step A (4 g, 13 mmol) andR,R-(+)-BPE (1,2-bis(phospholano)ethane)-Rh catalyst (0.08 9) in MeOH(60 mL) was placed into a Parr high pressure reactor and subjected tohydrogenation under 410 psi for three days. The MeOH was removed byevaporation, and the residue was purified on a column (1:1 hexane:EtOAc)to yield an oil which turned to solid on standing overnight.

MH⁺308.1

Step C

To a solution of the solid isolated in Step B (4.5 g, 14.5 mmol) in MeOH(30 mL) was added 1 N NaOH (14.5 mL, 14.5 mmol). The reaction mixturewas stirred at room temperature overnight. The MeOH was evaporated, andresulting solution was extracted with EtOAc (200 mL). The organic layerwas washed with dilute aqueous HCl solution, NaHCO₃ solution, and NaClsolution, dried with MgSO₄, and evaporated to yield a colorless oil.

MH⁺394.1, MH⁻392.0

Step D

To an ice cooled solution of the oil isolated in Step C (3.8 g, 13mmol), N,O-dimethylhydroxylamine·HCl salt (1.4 9,15 mmol), and HOBT (2g, 16 mmol) in CH₂Cl₂ (100 mL) was added TEA (3.6 mL) followed byaddition of EDC (3.0 g, 16 mmol). The reaction mixture was allowed towarm to room temperature and was stirred overnight. EtOAc (100 mL) wasadded, and the reaction mixture was then washed with citric acidsolution, NaHCO₃ solution, and NaCl solution. The organic layer wasseparated, dried with MgSO₄, and evaporated to yield a colorless oil.The crude oil product was used without further purification.

MH⁺337.1

Step E

To an ice cooled solution of the oil isolated in Step D (4.3 g, 13 mmol)in THF (200 mL) was slowly added LAH (1M solution in THF, 14 mL) whilekeeping the temperature below 5° C. The ice bath was removed, and thereaction mixture was stirred at room temperature for 20 min. A solutionof NaHSO₄ (1.5 g) in water (5 mL) was slowly added to quench thereaction. The reaction mixture was then filtered through Celite®. Then,EtOAc (200 mL) was added, and the organic layer was washed with NaClsolution, dried with MgSO₄ and evaporated to yield an oil. The crude oilproduct was used without further purification.

MH⁺278.0

Step F

To an ice cooled solution of trimethyl phosphonoacetate (6.4 mL, 13mmol) in THF (200 mL) was added 60% NaH in mineral oil (1.1 g, 26 mmol)in portions. The ice bath was removed, and the reaction mixture wasstirred at room temperature for 30 min. The solution was cooled to 0° C.again before a solution of the oil isolated in Step E (3.8 g, 13 mmol)in THF (100 mL) was added. The cooling bath was removed, and thereaction mixture was stirred at room temperature for another 20 min.Water (50 mL) was added, and most of THF was evaporated. The product wasextracted into EtOAc (200 mL), and the organic layer was washed withNaCl solution, dried with MgSO₄, and evaporated to yield a residue.Purification by column chromatography (1:1 heptane:EtOAc) yielded an oilwhich turned to a white solid upon standing.

MH⁺334.1

Step H

A solution of the solid isolated in Step G (2.7 g, 8 mmol), 10% Pd/C(2.7 g), Boc anhydride (1.83 g, 8 mmol), and 1,4-cyclohexadiene (7.5 mL,80 mmol) in EtOH (50 mL) was stirred at room temperature for 3 hours.The catalyst was removed by filtration, and the EtOH was evaporated toyield an oil

MH⁺302.2, MH⁺202.2 (M-Boc)

Step I:

A solution of the oil isolated in Step H (2.5 g, 8 mmol) in MeOH (20 mL)and 1 N NaOH (8.0 mL) was stirred at room temperature overnight. Thenthe pH was adjusted to about pH 2 by the addition of dilute HClsolution. The MeOH was removed in vacuo, and the product was extractedinto EtOAc (100 mL). The organic layer was washed with NaCl solution,dried with MgSO₄, and evaporated to yield an oil.

MH⁻286.1

Step J

To an ice cooled solution of N-methylcyclohexylamine (1.1 mL, 8 mmol),the oil isolated in Step 1 (2.1 g, 7.3 mmol), and HOBT (1.1 g, 8 mmol)in CH₂Cl₂ (100 mL) was added TEA (2 mL) followed by addition of EDC (1.5g, 8 mmol). The reaction mixture was allowed to warm to room temperatureand then was stirred overnight. Then, EtOAc (100 mL) was added. Theorganic solution was washed by citric acid solution, NaHCO₃ solution,and NaCl solution. The organic layer was dried with MgSO₄ and evaporatedto yield a brown oil. The crude oil product was used without furtherpurification.

MH⁺383.2, MH⁺283.1 (M-Boc)

Step K

A solution of the oil isolated in Step J (2.44 g, 6.4 mmol) in 20%TFA:CH₂Cl₂ (50 mL) was stirred at room temperature for 30 min. Thesolvent and most of the TFA was evaporated to give a residue to whichEtOAc (100 mL) was added. The reaction mixture was washed with NaHCO₃solution and NaCl solution. The organic layer was dried with MgSO₄ andevaporated to yield a brown oil.

MH⁺283.2

Step L

To a solution of the oil isolated in Step K (1.3 g, 4.6 mmol),2-nitro-5-phenoxybenzaldehyde (1.2 g, 4.9 mmol) and HOAc (0.28 mL) in1,2-dichloroethane (20 mL), was added NaBH(OAc)₃ (0.57 g, 9 mmol). Thereaction mixture was stirred at room temperature overnight. The reactionmixture was poured into 1 N NaOH (10 mL), and the resulting mixture wasextracted with EtOAc (100 mL). The organic layer was dried with MgSO₄and evaporated to yield a residue. The residue was purified by columnchromatography (1:1 heptane/EtOAc) to yield a colorless oil.

MH⁺510.1

Step M

To a solution of the oil isolated in Step L (0.6 g, 1.2 mmol) in MeOH(20 mL) was added 10% Pd/C (0.06 g) under N₂. The mixture washydrogenated at 10 psi for two hours. The catalyst was removed byfiltration, and the MeOH was evaporated. Purification by preparative TLC(100% EtOAc) yielded a. colorless oil.

(MH⁺480.2)

Step N

The oil isolated in Step M was dissolved in EtOH (5 mL), and BrCN (3Msolution in CH₂Cl₂, 0.16 mL) was added. The reaction mixture was stirredat room temperature overnight, and then the EtOH was evaporated. Theresulting residue was stirred in diethyl ether (50 mL) for 30 min. Theresulting solid was collected and recrystallized from diethylether/ethyl acetate (4:1) to yield the title compound as a yellow solidas its HBr salt.

MH⁺519.5

¹H NMR (300 MHz, CDCl₃): δ1.1-2.0 (m, 18H), 2.15-2.21 (m, 1H), 2.60-2.71(m, 1H), 2.82 (s, 0.37×3H), 2.90 (s, 0.63×3H), 3.18-3.51 (m, 3H),3.83-4.00 (m, 2H), 6.77 (s, 1H), 6.91 (d, J=8 Hz, 2H), 7.11 (t, J=5.8Hz, 1H), 7.27 (m, 3H), 8.22 (s, 1H).

EXAMPLE 33 (S)-enantiomer of4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-5-hydroxy-pentanoic acidcyclohexyl-methyl-amide (Compound #558)

Step A

To an ice cooled solution of N-methylcyclohexylamine (3.4 mL, 26 mmol),N-carbobenzyloxy-D-glutamic acid methyl ester (6 g, 20 mmol), and HOBT(3.6 g, 26 mmol) in CH₂Cl₂ (200 mL), was added TEA (6 mL) followed bythe addition of EDC (6.0 g, 30 mmol). The reaction mixture was allowedto warm to room temperature and stirred overnight. EtOAc (200 mL) wasadded to the reaction mixture. The resulting solution was washed bycitric acid solution, NaHCO₃ solution, and NaCl solution. The organiclayer was separated, dried with MgSO₄, and evaporated to yield an oil.The crude oil product was used without further purification.

MH⁺391.2

Step B

LiBH₄ (2M solution in THF, 20 mL, 40 mmol) was added to a solution ofthe oil isolated in Step A (8 g, 20 mmol) in THF (100 mL). The resultingsolution was refluxed under N₂ for 8 hours and then was stirred at roomtemperature overnight. Most of THF was removed under vacuum, and EtOAc(300 mL) was added to the residue. The EtOAc layer was washed by aqueousNaCl solution, dried with MgSO₄, and evaporated to yield a colorlessoil.

MH⁺363.1

Step C

To a solution of the oil isolated in Step B (7.5 g, 20 mmol) in MeOH(100 mL) was added 10% Pd/C (0.8 g) under N₂. The reaction mixture washydrogenated at 5 psi for 20 hours. The catalyst was removed byfiltration, and the MeOH was evaporated to yield a colorless oil.

MH⁺229.2

Step D

To a solution of the oil isolated in Step C (6 g, 26 mmol),2-nitro-5-phenoxybenzaldehyde (6.4 g, 26 mmol) and HOAc (1.6 mL) in1,2-dichloroethane (150 mL), was added NaBH₃CN (2.5 g, 40 mmol). Thereaction mixture was stirred at room temperature over the weekend. Thenthe reaction mixture was poured into 1 N NaOH (50 mL) and extracted withEtOAc (2×100 mL). The organic extracts were combined, dried with MgSO₄,and evaporated to yield a residue. Purification by column chromatography(1:1 heptane:EtOAc) yielded a yellow oil.

MH⁺456.1

Step E

To a solution of the oil isolated in Step D (6.3 g, 20 mmol) in MeOH(100 mL) was added 10% Pd/C (0.6 g) under N₂. The reaction mixture washydrogenated at 5 psi for 3 hours. The catalyst was removed byfiltration, and the MeOH was evaporated to yield a brown oil.

MH⁺426.3

Step F

A solution of the oil isolated in Step E (0.5 g, 1.2 mmol) and BrCN (3Msolution in CH₂Cl₂, 0.4 mL) in EtOH (50 mL) was stirred at roomtemperature overnight. The EtOH was evaporated to yield an oil which wasstirred in diethyl ether (100 mL) for one hour. The resulting solid wascollected to yield the title compound as a solid as its HBr salt.

MH⁺451.2

¹H NMR (300 MHz, CDCl₃): δ1.0-1.9 (m, 12H), 2.35 (m, 2H), 2.75 (d,J=3.22 Hz, 3H), 3.4 (m, 1H), 3.6-3.8 (m, 2H), 4.27-4.36 (m, 2H), 4.6 (d,J=14.5 (m, 2H), 7.3 (t, J=8.04 Hz, 2H).

EXAMPLE 34 (S)-enantiomer of2-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-pentanedioic acidbis-(cyclohexyl-methyl-amide) (Comnpound #634)

Step A

To a solution of the material prepared as in Example 33, Step A (7.5 g,19 mmol) in MeOH (40 mL) was added 1 N NaOH (24 mL, 24 mmol). Thereaction mixture was stirred at room temperature overnight and then wasacidified with citric acid (10 g). The MeOH was removed by vacuum. Theresulting solution was extracted with EtOAc (2×200 mL). The combinedorganic layers were washed with NaCl solution, dried with MgSO₄, andconcentrated to yield an oil.

MH⁻375.0

Step B

To an ice cooled solution of N-methylcyclohexylamine (0.31 mL, 2.2mmol), the oil isolated in Step A (0.8 g, 2.1 mmol), and HOBT (0.4 g, 3mmol) in CH₂Cl₂ (50 mL), was added TEA (0.6 mL) followed by addition ofEDC (0.6 g, 3 mmol). The reaction mixture was allowed to warm to roomtemperature and then was stirred overnight. EtOAc (100 mL) was thenadded, and the reaction mixture was washed with citric acid solution,NaHCO₃ solution, and NaCl solution. The organic layer was dried withMgSO₄ and evaporated to yield an oil. The crude oil product was usedwithout further purification.

MH⁺472.5

Step C

To a solution of the oil isolated in Step B (1.0 g, 2.1 mmol) in MeOH(40 mL) was added 10% Pd/C (0.1 g) under N₂. The mixture washydrogenated at 5 psi overnight. The catalyst was removed by filtration,and MeOH was evaporated to yield a colorless oil.

MH⁺338.3

Step D

To a solution of the oil isolated in Step D (0.7 g, 21 mmol),2-nitro-5-phenoxybenzaldehyde (0.5 g, 21 mmol) and HOAc (0.12 mL) in1,2-dichloroethane (20 mL), was added NaBH₃CN (0.25 g, 4 mmol). Thereaction mixture was stirred at room temperature over the weekend. Thereaction mixture was poured into 1 N NaOH (50 mL) and extracted withEtOAc (100 mL). The organic layer was dried over MgSO₄ and evaporated toyield a residue. The residue was purified on a column (1:1heptane:EtOAc) to yield an oil.

MH⁺565.6

Step E

To a solution of the oil isolated in Step D (0.56 g, 1 mmol) in MeOH (20mL), 10% Pd/C (0.05 g) was added. The reaction mixture was hydrogenatedat 5 psi for 2 hours. The catalyst was removed by filtration, and theMeOH was evaporated. Purification by preparative TLC yielded a colorlessoil.

MH⁺535.3

Step F

A solution of the oil isolated in Step E (0.15 g, 0.3 mmol) and BrCN (3Msolution in CH₂Cl₂, 0.1 mL) in EtOH (10 mL) was stirred at roomtemperature overnight. The EtOH was evaporated, and the resulting oilwas stirred in diethyl ether (50 mL) for one hour. The resulting solidwas collected to yield the title compound as a solid as its HBr salt.

MH⁺560.3

¹H NMR (300 MHz, CDCl₃): δ1.0-2.1 (m, 22H), 2.35 (m, 2H), 2.63 (s, 3H),2.82 (s, 3H), 2.7-2.9 (m, 2H), 3.4 (m,1H), 3.99 (m,1H), 4.3 (m, 2H),4.86 (m, 1H), 6.6-7.3 (m, 8H).

EXAMPLE 353-[2-Amino-6-(3-methyl-butoxy)-4H-quinazolin-3-ylmethyl]-N-cyclohexyl-N-methyl-benzamide(Compound #517)

Step A

To a reaction vessel containing isoamyl alcohol (44 mg, 0.5 mmol),triphenylphosphine (197 mg, 0.75 mmol) in THF (1 mL), and5-hydroxy-2-nitrobenzaldehyde (125 mg, 0.75 mmol) in THF (1 mL) wasadded diisopropylazodicarboxylate (148,uL, 0.75 mmol) at 0° C. Therecaton mixture was allowed to warm to room temperature and then wasstirred at 25° C. for 3 h. The solvent was removed in vacuo, and theresulting residue was purified by reverse-phase chromatography to yieldan oil.

Step B

To a solution of the oil isolated in Step A (62 mg, 0.26 mmol) in DCE(0.75 mL) was added 3-aminomethyl-N-cyclohexyl-N-methyl-benzamide (79mg, 0.32 mmol) in DCE (0.75 mL) followed by addition of HOAc (15 μL).The reaction mixture was stirred at 25° C. for 30 min, and thenNaBH(OAc)₃ (93 mg, 0.44 mmol) in DMF (0.3 mL) was added. The reactionmixture was stirred at 25° C. for 20 h. After quenching with H₂O, thesolvent was removed in vacuo to yield crude product.

Step C

To a solution of the crude product isolated in Step B in ethanol (2 mL)was added zinc dust (588 mg, 9 mmol) and NH₄Cl (120 mg, 2.25 mmol). Thereaction mixture was irradiated (gwave) at 85° C. for 10 min. Theinsolubles were removed by filtration and washed with ethanol (1 mL).

Step D

To the filtrate isolated in Step C was added cyanogen bromide (0.36 mL,1.8 mmol, 5M solution in CH₃CN). The reaction mixture was stirred at 25°C. for 18 h. After quenching with 3M NaOH (0.4 mL), the reaction mixturewas concentrated. The resulting residue was taken up in 1% TEA:CH₂Cl₂(0.8 mL) and H₂O (0.35 mL). The solution was absorbed onto diatomaceousearth and eluted with 1% triethylamine/ethyl acetate. The eluate wasconcentrated to a residue and purified by reverse-phase chromatographyto yield the title compound as an oil, as its correspondingtrifluoroacetate salt.

MS m/z (MH⁺) calcd 463.3, found 463.5

EXAMPLE 36N-Cyclohexyl-3-[2-methoxyamino-6-(2-methoxy-phenyl)-4H-quinazolin-3-ylmethyl]-N-methyl-benzamide(Compound #605)

Step A

To a round-bottomed flask containing KNO₃ (14.3 g, 0.14 mol) in H₂SO₄(109 mL) was added 3-bromobenzaldehyde (25 g, 0.14 mol), over 15 min, at0° C. The reaction mixture was vigorously stirred at 0° C. for 20 min,poured onto crushed ice (600 mL), and extracted with DCM (3×). Thecombined organic layers were dried, filtered, and concentrated in vacuo.The residue was recrystallized from EtOAc/hexane to yield a yellowsolid.

Step B

To a flask containing 3-cyanobenzoic acid (10 g, 0.068 mol) in DCM (300mL) was added diisopropyl ethylamine (47 mL, 0.27 mol) andN-methylcyclohexyl amine (13.3 mL, 0.1 mol) with stirring. The resultingsolution was cooled to approximately 0° C., and then2-chloro-1,3-dimethylimidazolium chloride (23 g, 0.14 mol) was addedwith stirring. After 5 minutes the cooling bath was removed and thereaction mixture was stirred toward room temperature for 4 h. Thereaction was quenched with 100 mL of water, transferred to a separatoryfunnel, mixed, and the layers were separated. The aqueous layer wasextracted with DCM (2×100 mL), and the combined organic layers weredried over Na₂SO₄, filtered, concentrated to a residue, and placed undervacuum (˜1 mm Hg) for 1 h to yield a residue.

Step C

The residue prepared in Step B was transferred to a Parr bottle withEtOH (250 mL) and then degassed and blanked with nitrogen before 12NHCl_((aq)) (28 mL, 0.34 mol) and 10% Pd/C (1.6 g) slurried in water wereadded. The slurry was exposed to 50 psi of H₂ for 14 h at roomtemperature using standard Parr techniques and then degassed withnitrogen for 5 minutes and filtered through a pad of Celite®. Thereaction mixture was then concentrated to the aqueous layer andtransferred to a separatory funnel with water (100 mL) and DCM (50 mL).The layers were separated and the aqueous layer was extracted with DCM(2×25 mL). The combined organic layers were extracted with 0.5N HCl (25mL). The layers were separated, and the combined aqueous layers wereadjusted to pH>9 with 3N NaOH and extracted with DCM (5×50 mL). Thecombined organics were dried over Na₂SO₄, filtered, concentrated to aresidue, and placed under vacuum (˜1 mm Hg) for 1 day. This two-stepprocedure yielded a residue contaminated by diisopropyl ethyl amine butof sufficient purity for subsequent chemical transformations.

MS m/z (MH⁺) calcd 247.2, found 247.3

Step D

To a round-bottomed flask containing the residue isolated in Step C (6.7g, 0.032 mol) in DCE (175 mL) was added the material isolated in Step A(7.4. g, 0.032 mol). After stirring at room temperature for 30 min,NaBH(OAc)₃ (13.7 g, 0.065 mol) was added, and the reaction mixture wasstirred at room temperature for 18 h. The reaction was quenched with 1 NNaOH (100 mL). The layers were separated and the aqueous layer wasextracted with DCM (3×25 mL). The combined organic layers were driedover MgSO₄, filtered, and concentrated in vacuo to constant weight. Theresulting residue (14.7 g) was greater than 95% pure by LC/MS analysisand used in subsequent reactions without further purification.

MS m/z (MH⁺) calcd 460.1, found 460.4

Step E

To a solution of the residue isolated in Step D (543 mg, 1.18 mmol) inethyl alcohol (5 mL) was added potassium carbonate (245 mg, 1.77 mmol)in water (0.25 mL), 2-methoxyphenylboronic acid (269 mg, 1.77 mmol), andbis(diphenyl-phosphino)ferrocene dichloropalladium (96 mg, 0.118 mmol).The reaction mixture was irradiated (μwave) at 100° C. for 10 min. Aftercooling to room temperature, the resulting solution was used directly inthe following step.

MS m/z (MH⁺) calcd 488.3, found 488.6

Step F

To the above filtered solution from Step E was added NH₄Cl (0.63 g, 11.8mmol) and Zn (1.5 g, 23.6 mmol). The reaction slurry was irradiated(lwave) at 80° C. for 15 min. After cooling to room temperature, thereaction mixture was filtered and concentrated. The resulting residuewas purified by column chromatography on silica gel (10% EtOAc/heptanecontaining 1% Et₃N) to 60% EtOAc/heptane containing 1% Et₃N) to yield awhite solid.

MS m/z (MH⁺) calcd 458.3, found 458.7

Step G

To a round bottom flask fitted with a reflux condenser was added thesolid isolated in Step F (0.122 g, 0.267 mmol) dissolved in ethanol (4mL) and carbon disulfide (6 mL). The resulting solution was heated atreflux for 4 h, cooled to room temperature, and concentrated. Theresulting residue was purified by column chromatography on silica gel(2% EtOAc/heptane to 30% EtOAc/heptane) to yield a white solid.

HRMS (ES-TOF) calcd. for C₃₀H₃₄N₃O₂S m/z 500.2372 (M+H), found: 500.2

Step H

To a solution of the solid isolated in Step G (42.7 mg, 0.09 mmol) inCH₃CN (0.2 mL) was added CH₃1 (0.021 mL, 0.34 mmol). The resultingsolution was stirred at room temperature for 3 h, concentrated to aresidue, and dried for 1 h at <1 mmHg to yield a residue.

Step I

To the residue isolated in Step H dissolved in MeOH (0.2 mL) was addedMeONH₂HCl (0.016 g, 0.19 mmol), NaHCO₃ (0.016 g, 0.19 mmol), and AgOAc(0.016 mg, 0.10 mmol). The resulting solution was stirred at.70° C. for2 h, cooled to room temperature and concentrated. The resulting residuewas suspended in water (1 mL) and extracted with EtOAc (4×0.5 mL). Thecombined organic layers were dried (Na₂SO₄) and concentrated. Theresulting residue was purified by preparative RP-HPLC to yield an oil,which was determined to be pure product, as well as an additionalresidue, which was determined to be 70% pure.

HRMS (ES-TOF) calcd. for C₃₁H₃₇N₄O₃ m/z 513.2866 (M+H), found: 513.3

EXAMPLE 37 Butane-1-sulfonic acid[2-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-ethyl]-amide (Compound #135)

To a solution of the intermediate prepared as in Example 18, Step D(0.16 mmol) in 5 mL of dioxane was added TEA (42 mg, 0.48 mmol) followedby n-butyl sulfonyl chloride (22 mg, 0.14 mmol). The reaction mixturewas stirred at room temperature for 3 days. The solvent was removed invacuo, and the resulting residue was purified on a Gilson to yield thetitle compound as a yellow solid.

MH⁺430.2

¹H NMR (300 MHz, DMSO-d₆): δ0.86 (t, J=7.21Hz, 3H), 1.36 (q, J=7.20 Hz,2H), 3.00 (t, J=7.67 Hz, 2H), 3.23-3.55 (m, 4H), 4.62 (s, 2H), 6.90-7.41(m, 9H), 7.80 (br s, 2H).

EXAMPLE 381-Adamantan-1-yl-3-[2-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-ethyl]-urea(Compound #206)

To a solution of the intermediate prepared as in Example 18, Step D(16.3 mg, 0.137 mmol) in dioxane (5 mL) was added TEA (0.28 mL, 0.41mmol) followed by 1-adamantyl isocyanate (26.3 mg, 0.137 mmol). Thereaction mixture was stirred overnight at room temperature. The solventwas removed in vacuo, and the resulting residue was purified by HPLC toyield the title compound as a white solid.

MH⁺430.2

¹H NMR (300 MHz, DMSO-d₆): δ1.58-1.96 (m, 15H), 3.24-3.43 (m, 4H), 4.59(s, 2H), 5.83 (s, 1H), 5.88 (t, 1H), 6.87-7.41 (m, 8H), 7.90 (s, 2H).

EXAMPLE 391-Adamantan-1-yl-3-[2-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-ethyl]-thiourea(Compound #214)

To a solution of the intermediate prepared as in Example 18, Step D(0.133 mmol) in dioxane (5 mL) was added TEA (0.27 mL, 0.40 mmol)followed by 1-adamantyl isothiocyanate (25.7 mg, 0.133 mmol). Thereaction mixture was stirred overnight at room temperature. The solventwas removed in vacuo, and HLPC analysis of the resulting residueindicated mainly unreacted amine was present. The material wasre-dissolved in dioxane (5 mL) and then TEA (0.27 mL, 0.40 mmol) wasadded followed by 1-adamantyl isothiocyanate (25.7 mg, 0.133 mmol). Thereaction mixture was refluxed for 3 h and then was stirred at roomtemperature overnight. The solvent was removed in vacuo, and theresulting residue was purified by HPLC to yield the title compound as awhite solid.

MH⁺476.2

¹H NMR (300 MHz, DMSO-d₆): δ1.59-2.06 (m, 15H), 3.69 (m, 4H), 4.61 (s,2H), 6.89-7.40 (m, 10H), 7.82 (s, 2H).

EXAMPLE 40 [2-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-ethyl]-carbamicacid isopropyl ester (Compound #220)

To a solution of the intermediate prepared as in Example 18, Step D(0.133 mmol) in dioxane (5 mL) was added TEA (40.3 mg, 0.40 mmol)followed by isopropyl chloroformate (0.133 mL, 0.133 mmol) as a 1.0Msolution in toluene. The rection mixture was stirred overnight at roomtemperature. The solvent was removed in vacuo to yield a residue thatwas purified by HPLC to yield the title compound as a white solid.

MH⁺369.1

¹H NMR (300 MHz, DMSO-d₆): δ1.11 (d, J=6.22 Hz, 6H), 3.29 (m, 4H), 4.58(s, 3H), 4.64 (m, 1H), 6.88-7.41 (m, 9H), 7.85 (s, 2H).

EXAMPLE 41 3-[3-(Cyclohexyl-methyl-amino)-propyl]-6-phenoxy-3,4-dihydroquinazolin-2-ylamine (Compound #428)

Step A

To a solution of N-(3-bromopropyl)phthalimide (1.61 g, 6 mmol) in 10 mLof DMF was added N-methylcyclohexylamine (2.04 g, 18 mmol). The reactionmixture was heated at 100° C. for 4 h. The reaction mixture was cooledto room temperature and concentrated in vacuo. To the resulting residuewas added water (10 mL). The resulting solution was extracted with EtOAc(3×30 mL). The organic extracts were combined, washed with brine, andevaporated to yield a brown oil.

MH⁺301.1

Step B

A solution of the oil isolated in Step A (1.61 g, 5.32 mmol) andhydrazine monohydrate (0.532 g, 10.64 mmol) in methanol was refluxed 3h. The reaction mixture was concentrated, and water (50 mL) was added tothe residue. The resulting solution was acidified with 1 N HCl. Thereaction mixture was then extracted with EtOAc (4×50 mL). The aqueouslayer was basified with NaHCO₃ and then was extracted with EtOAc (3×50mL). The EtOAc extracts were combined, dried (Na₂SO₄), and concentratedto a residue. The residue did not have the molecular weight of thedesired product so the aqueous layer was basified with aqueous ammonia.The resulting solution was extracted with EtOAc (3×50 mL). The organicextracts were combined, washed with brine, dried (Na₂SO₄), andconcentrated to yield a clear oil.

MH⁺171.3

Step C

A solution of the oil isolated in Step B (0.28 g, 1.6 mmol) and2-nitro-5-phenoxybenzaldehyde (0.27 g, 1.1 mmol) in DCE was stirred for30 minutes. Then NaBH(OAc)₃ (0.34 g, 1.6 mmol) was added, and thereaction mixture was stirred overnight. The reaction mixture wasquenched with 1 N NaOH (4 mL), and then water (10 mL) was added. Theresulting solution was extracted with CH₂Cl₂ (3×15 mL). The CH₂Cl₂extracts were combined, washed with brine, dried (MgSO₄), andconcentrated to a residue. Purification by flash chromatography 5% (2NNH₃ in MeOH) in CHCl₃ yielded a yellow oil.

MH⁺398.3

Step D

A solution of the oil isolated in Step C (0.31 g) and palladium oncarbon (60 mg) in EtOH (50 mL) was hydrogenated at 40 psi in a Parrshaker for 3 h. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure to yield a residue.

MH⁺368.3

Step E

To a solution of the residue isolated in Step D (0.78 mmol) in EtOH (20mL) was added cyanogen bromide in 1 mL of EtOH. The reaction mixture wasstirred at room temperature overnight and then refluxed for 3 h. Thereaction mixture was cooled and filtered to yield the title compound asan off-white solid.

MH⁺393.2

¹H NMR (300 MHz, DMSO-d₆): δ0.90-2.00 (m, 12H), 2.70 (d, 3H), 2.90-3.40(m, 5H), 4.61 (s, 2H), 6.90-7.42 (m, 8H), 7.89 (br s, 2H).

EXAMPLE 42[2-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-ethyl]-methyl-carbamic acidtert-butyl ester (Compound #425)

Step A

A solution of N-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester(0.33 g, 1.90 mmol) and 2-nitro-5-phenoxybenzaldehyde (0.31 g, 1.27mmol) in DCE was stirred for 30 minutes. Then NaBH(OAc)₃ (0.40 g, 1.90mmol) was added, and the reaction mixture was stirred overnight. Thereaction mixture was quenched with 1 N NaOH (4 mL), and then water (10mL) was added. The resulting solution was extracted with CH₂Cl₂ (3×15mL). The CH₂Cl₂ extracts were combined, washed with brine, dried(MgSO₄), and concentrated to a residue. Purification by flashchromatography yielded an oil.

MH⁺401.5

Step B

A solution of the oil isolated in Step A (0.40 g) and palladium oncarbon (80 mg) in EtOH was hydrogenated at 45 psi in a Parr shaker for 3h. The reaction mixture was filtered, and the filtrate was concentratedunder reduced pressure to yield a residue.

MH⁺372.3

Step C

To a solution of the residue isolated in Step B (0.36 g, 0.97 mmol) inEtOH (20 mL) was added cyanogen bromide (0.113 g, 1.07 mmol) in 1 mL ofEtOH. The reaction mixture was stirred at room temperature overnight andthen refluxed for 3 h. The reaction mixture was cooled and concentratedto yield a residue. Purification by reverse phase HPLC yielded the titlecompound as a white solid.

MH⁺397.2

¹H NMR (300 MHz, DMSO-d₆): δ1.20 (d, 9H), 2.81 (s, 3H), 3.30 (m, 4H),4.56 (s, 2H), 6.92-7.40 (m, 8H), 7.84 (br s, 2H)

EXAMPLE 43 Cyclohexanecarboxylic acid[2-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-ethyl]-methyl-amide (Compound#426)

Step A

A solution of the solid prepared as in Example 40, Step C (0.153 g) inTFA (15 mL) was stirred at room temperature for 3 h. The resultingsolution was concentrated in vacuo to yield a residue.

Step B

To a solution of the residue isolated in Step A (0.26 mmol) and TEA (80mg, 0.79 mmol) in dioxane (10 mL) was added cyclohexanecarbonyl chloride(38.0 mg, 0.26 mmol). The reaction mixture was stirred overnight at roomtemperature. The resulting solution was concentrated in vacuo to yield aresidue. The residue was purified by HPLC to yield the title compound asa white solid.

MH⁺407.3

¹H NMR (300 MHz, DMSO-d₆): δ1.00-2.00 (m, 11H), 3.01 (br s, 3H), 3.5 (m,4H), 4.60 (s, 2H), 6.80-7.40 (m, 8H), 7.9 (br s, 2H).

EXAMPLE 444-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-piperidine-1-carboxylic acidtert-butyl ester (Compound #499)

Step A

A solution of 4-amino-1-Boc-piperidine (0.60 g, 3.0 mmol) and2-nitro-5-phenoxybenzaldehyde (0.48 g, 2.0 mmol) in DCE was stirred for30 minutes. Then NaBH(OAc)₃ (0.64 g, 3.0 mmol) was added, and thereaction mixture was stirred overnight. The reaction mixture wasquenched with 1 N NaOH (10 mL), and the resulting solution was extractedwith CH₂Cl₂ (2×20 mL). The CH₂Cl₂ extracts were combined, washed withbrine, dried (MgSO₄), and concentrated to a residue. Purification byflash chromatography (10% to 40% EtOAc-hexanes) yielded an oil.

Step B

A solution of the oil isolated in Step A (0.67 g) and palladium oncarbon (130 mg) in EtOH was hydrogenated at 40 psi in a Parr shaker for3 h. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure to yield a residue.

Step C

To a solution of the residue isolated in Step B (0.97 mmol) in EtOH wasadded cyanogen bromide (0.183 g, 1.73 mmol). The reaction mixture wasstirred at room temperature overnight and then refluxed for 1 h. Thereaction mixture was cooled and concentrated to yield a residue.Recrystallization of the residue from EtOH yielded the title compound asan off-white solid.

MH⁺423.2

¹H NMR (300 MHz, DMSO-d₆): δ1.41 (s, 9H), 1.69 (m, 4H), 2.81 (m, 2H),4.09 (m, 3H), 4.48 (s, 2H), 6.95-7.42 (m, 8H), 7.88 (s, 2H)

EXAMPLE 45[[4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-piperidin-1-yl]-cyclohexyl-methanone(Compound #522)

Step A

A solution of the solid prepared as in Example 44, Step C (0.350 9) inTFA (20 mL) was stirred at room temperature for 5 h. The resultingsolution was concentrated in vacuo to yield a residue.

Step B

To a solution of the residue isolated in Step A (0.23 mmol) and TEA (70mg) in dioxane (5 mL) was added cyclohexanecarbonyl chloride (34 mg).The reaction mixture was stirred overnight at room temperature. Theresulting solution was concentrated in vacuo to yield the title compoundas a yellow solid.

MH⁺433.2

¹H NMR (300 MHz, DMSO-d₆): δ1.00-2.01 (m, 15H), 3.4 (m, 2H), 4.1 (m,2H), 4.5 (m, 3H), 6.9-7.4 (m, 8H), 7.9 (br s, 2H)

EXAMPLE 46 (R)-enantiomer of cyclohexanecarboxylic acid[2-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-1-cyclohexyl-ethyl]-amide(Compound #636)

Step A

To a solution of 5-fluoro-2-nitrobenzoic acid (6.1 g, 33.0 mmol) intoluene (10 mL) was added thionyl chloride (8.0 mL, 110. mmol). Thereaction mixture was refluxed for 3.5 h. The solvent was thenevaporated, and the resulting residue was poured into 28% aqueousammonia solution (30 mL). A yellow solid formed which was extracted intoethyl acetate. The ethyl acetate solution was washed with brine, dried(Na₂SO₄), and concentrated to yield a residue. The residue wasrecrystallized from ethyl acetate and hexanes to yielda yellow solid.

Step B

A solution of the yellow solid isolated in Step A (6.13 g, 33.3 mmol),phenol (3.14 g, 33.4 mmol), and K₂CO₃ (5.52 g, 40.0 mmol) in DMF (30 mL)was heated at 130° C. for 2 h. The DMF was evaporated to yield a yellowsolid that was washed with hexane. Purification by HPLC yielded a yellowsolid.

Step C

To a solution of the yellow solid isolated in Step B (4.0 g, 15.5 mmol)in THF (10 mL) was added BH₃,THF (1 M solution in THF, 80 mL). Thereaction mixture was refluxed overnight. The reaction mixture was cooledto 0° C., and then concentrated HCl (20 mL) was added. The resultingsolution was refluxed 1 h and then cooled. The THF was evaporated, andNaOH solution (100 mL) was added. The resulting solution was extractedwith CH₂Cl₂ (3×100 mL). The organic extracts were combined, washed withbrine (100 mL), and dried (MgSO₄). Concentration yielded crude productthat was purified by column chromatography (100% EtOAc) to yield aresidue.

Step D

To a mixture of N-Boc-D-cyclohexylglycine (2.40 g, 9.33 mmol) andN,O-dimethylhydroxylamine hydrochloride (0.91 g, 9.4 mmol) was added DMF(10 mL) and TEA (1.9 g, 18.66 mmol) followed by HBTU (3.6 g, 9.4 mmol).The reaction mixture was stirred at room temperature overnight. Thereaction was quenched with water (50 mL) and then was extracted withEtOAc (3×50 mL). The organic extracts were combined, washed with brine(3×50 mL) and concentrated to an oil containing some solid. ¹H NMRindicated that the product was contaminated with HBTU. The crudematerial was dissolved in EtOAc (60 mL) and was washed with 1 N HCl (10mL), water (3×10 mL), and brine (30 mL). The resulting solution wasdried and concentrated to yield a residue.

Step E

A solution of LAH (0.37 g, 9.6 mmol) in 20 mL of THF was cooled to about0C. Then a solution of the residue isolated in Step D (2.23 g, 7.4 mmol)in THF (20 mL) was added, and the reaction mixture was warmed to roomtemperature. The reaction mixture was stirred at room temperature for 20min and then was re-cooled to 0° C. The reaction was quenched with asolution of NaHSO₄ (1.8 g) in water (10 mL). The reaction mixture wasthen extracted with EtOAc (3×50mL). The organic extracts were combined,washed with brine, dried (MgSO₄), and concentrated under reducedpressure to yield a residue.

Step F

A solution of the residue isolated in Step E (1.54 g, 7.4 mmol) and theresidue isolated in Step C (1.82 g, 7.4 mmol) in DCE was stirred for 30minutes. Then NaBH(OAc)₃ (1.57 g, 7.4 mmol) was added, and the reactionmixture was stirred overnight. The reaction mixture vVas quenched with 1N NaOH (10 mL). The resulting solution was extracted with CH₂Cl₂ (3×30mL). The CH₂Cl₂ extracts were combined, washed with brine (1 ×30 mL),dried (MgSO₄), and concentrated to a residue. Purification by flashchromatography (30% EtOAc-hexanes) yielded an orange oil.

MH⁺470.2

Step G

A solution of the oil isolated in Step F (1.88 g) and palladium oncarbon (20 mg) in EtOH was hydrogenated at 45 psi in a Parr shaker for 3h. The reaction mixture was filtered through Celite®, and the filtratewas concentrated under reduced pressure to yield a residue.

MH⁺440

Step H

To a solution of the residue isolated in Step G (2.5 mmol) in EtOH (30mL) was added cyanogen bromide (0.278 g, 2.6 mmol). The reaction mixturewas stirred at room temperature for 1 h and then was refluxed for 3 h.The reaction mixture was cooled and concentrated to yield a residue.Recrystallization of the residue from EtOH yielded a solid. A secondrecrystallization was done to yield a second crop of product.

Step I

A solution of the solid isolated in Step H (0.24 g) in TFA (10 mL) wasstirred at room temperature for 5 h. The solution was concentrated invacuo to yield a residue.

Step J

To a solution of the residue isolated in-Step 1 (0.22 mmol) and TEA(55.1 mg, 0.55 mmol) in dioxane (10 mL) was added cyclohexanecarbonylchloride (33 mg, 0.22 mol). The reaction mixture was stirred for 2 h atroom temperature. The solution was concentrated in vacuo to yield thetitle compound as a white solid.

MH⁺475.5 ¹H NMR (300 MHz, DMSO-d₆): δ1.00-2.00 (m, 22H), 3.4 (m,.2H),4.0 (m, 1H), 4.5 (d, J=15.2 Hz, 2H), 4.6 (d, J=15.2 Hz, 2H), 6.8-7.4 (m,9H), 7.83 (br s, 2H)

EXAMPLE 473-[1-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-propyl]-N-cyclohexyl-N-methyl-benzamide(Compound #204)

Step A

A mixture of 3-propionylbenzoic acid (0.194 g, 1.09 mmol), HBTU (0.413g, 1.09 mmol), and N-ethylmorpholine (0.38 g, 3.38 mmol) in DMF (20 mL)was stirred for 15 minutes. Then N-methylcyclohexylamine (0.351 g, 3.11mmol) was added, and the reaction mixture was stirred over the weekend.With thorough mixing, 75 mL of 1 N HCl and EtOAc were added. The layerswere separated, and the organic layer was washed three times withsaturated aqueous NaCl solution. The organic layer was dried (Na₂SO₄),filtered and yield a a thick oil.

MH⁺274.2

Step B

A solution of the oil isolated in Step A (0.34 g, 1.25 mmol) andhydroxylamine (0.062 g, 1.88 mmol, 50% solution in water) in EtOH (10mL) was refluxed for 2.5 h. The reaction mixture was then cooled anddiluted with water (75 mL). The resulting mixture was extracted withEtOAc. The organic layer was separated, dried (Na₂SO₄), filtered, andevaporated to yield a residue.

Step C

A solution of the residue isolated in Step B (0.388 g, 1.35 mmol) andzinc (4.39 9) in HOAc (35 mL) was stirred overnight. After overnightstirring, the reaction mixture was filtered through Dicalite. Thefiltrate was evaporated to yield a residue. The residue was treated withexcess 3N NaOH, and the resulting solution was extracted with diethylether. The diethyl ether extract was dried (Na₂SO₄), filtered, andevaporated to yield an oil.

MH⁺275.2

Step D

A solution of the oil isolated in Step C (0.187 g, 0.68 mmol) and2-nitro-5-phenoxybenzaldehyde (0.165 g, 0.68 mmol) in DCE (3.5 mL) wasstirred for 15 minutes. Then NaBH(OAc)₃ (0.200 g, 0.94 mmol) was added,and the reaction mixture was stirred overnight. To the reaction mixturewas added 3N NaOH until the pH was basic. The resulting solution wasmixed thoroughly with CH₂Cl₂. The layers were separated, and the organiclayer was dried (Na₂SO₄), filtered, and evaporated to yield a thickresidue.

MH⁺502.5

Step E

A solution of the residue isolated in Step D (0.337 g, 0.67 mmol) andstannous chloride monohydrate (0.833 g, 3.69 mmol) in EtOH (4 mL) wasrefluxed for 2 h. The solution was cooled, and aqueous sodiumbicarbonate solution was added. EtOAc was added to this mixture, and themixture was filtered through Dicalite. The organic layer was separated,dried (Na₂SO₄), filtered, and evaporated to yield a thick brown oil.

MH⁺427.5

Step F

To a solution of the oil (0.068 g, 0.14 mmol) prepared in Step E in EtOH(4 mL) was added cyanogen bromide (0.025 g, 0.24 mmol). The reactionmixture was refluxed for 2 h. After cooling, the reaction mixture wasevaporated to yield a clear brown glass. The glass was triturated threetimes with diethyl ether. Filtration yielded the title compound as a tansolid.

EXAMPLE 482-(2-Amino-6-Phenoxy-4H-quinazolin-3-ylmethyl)-N-cyclohexyl-N-methyl-isonicotinamide(Compound #508)

Step A

A mixture of 2-cyano-4-pyridinecarboxylic acid (0.500 g, 3.38 mmol),HBTU (1.28 g, 3.38 mmol), and N-ethylmorpholine (1.21 g, 10.48 mmol) inDMF (35 mL) was stirred for 15 minutes. Then N-methylcyclohexylamine(1.089 g, 9.64 mmol) was added, and the reaction mixture was stirredovernight. Water (300 mL) was added to the reaction mixture. Theresulting solution was extracted with EtOAc. The layers were separated,and the organic layer was washed three times with saturated aqueous NaClsolution. The organic layer was dried (Na₂SO₄), filtered and evaporatedto yield a dark oil.

MH⁺244.1

Step B

Following the procedure described in J. Med. Chem. 1985, 28,164, asolution of the oil isolated in Step A (0.77 g), 10% palladium on carbon(0.260 g), and concentrated HCl (0.680 mL) in EtOH (30 mL) washydrogenated at 35 psi on a Parr shaker. After 2 h, hydrogen uptakeceased, and the reaction was stopped. The reaction mixture was filteredand evaporated to yield a tan solid. The tan solid was slurried inCH₂Cl₂, and then 3N NaOH was added with thorough mixing. The layers wereseparated, and the organic layer was dried (K₂CO₃), filtered, andevaporated to yield a light brown oil.

MH⁺248.2

Step C

A solution of the oil isolated in Step B (0.242 g, 1.0 mmol) and2-nitro-5-phenoxybenzaldehyde (0.238 g, 1.0 mmol) in DCE (10 mL) wasstirred for 15 minutes. Then NaBH(OAc)₃ (0.317 g, 1.5 mmol) was added,and the reaction mixture was stirred overnight. To the reaction mixturewas added 3N NaOH with thorough mixing. The CH₂Cl₂ layer was separated,and the organic layer was dried (Na₂SO₄), filtered, and evaporated toyield a thick orange oil.

MH⁺475.2

Step D

A solution of the oil isolated in Step C (0.484 g, 1.02 mmol) and 10%palladium on carbon (0.081 g) in EtOH (60 mL) was hydrogenated at 35 psion a Parr shaker. After 2.5 h, the reaction mixture was filtered andevaporated to yield a thick brown oil.

MH⁺445.2

Step E

To a solution of the oil (0.404 g, 0.91 mmol) prepared in Step D in EtOH(13 mL) was added cyanogen bromide (0.551 mL, 2.76 mmol) as a 5Msolution in MeCN. The reaction mixture was stirred at room temperatureovernight and then evaporated to yield a residue. The residue wastriturated several times with diethyl ether to yield a tan solid. Ofthis material, 100 mg was purified on flash silica gel using 90:10CH₂Cl₂:(0.5M NH₃ in MeOH) to yield a residue. This residue was dissolvedin CH₂Cl₂, and the resulting solution was washed with 3N NaOH solution.The organic layer was dried (Na₂SO₄) and filtered. To the filtrate wasadded TFA (1 mL), and the solution was evaporated to yield the titlecompound as a dark residue.

MH⁺470.0

EXAMPLE 49 5-(2-Amino-6-phenoxy-4H-quinazolin-3-ylmethyl)-furan-2-carboxylic acid cyclohexyl-methyl-amide (Compound #424)

Step A

A mixture of 5-formyl-2-furancarboxylic acid (0.153 g, 1.09 mmol), HBTU(0.413 g, 1.09 mmol), and N-ethylmorpholine (0.38 g, 3.38 mmol) in DMF(20 mL) was stirred for 15 minutes. Then N-methylcyclohexylamine (0.351g, 3.11 mmol) was added, and the reaction mixture was stirred overnight.With thorough mixing, 75 mL of 1 N HCl and EtOAc were added. The layerswere separated, and the organic layer was washed three times withsaturated aqueous NaCl solution. The organic layer was dried (Na₂SO₄),filtered, and evaporated to yield a thick oil.

MH⁺236.1

Step B

A solution of the oil isolated in Step A (0.257 g, 1.25 mmol) andhydroxylamine (0.062 g, 1.88 mmol, 50% solution in water) in EtOH (10mL) was refluxed for 2 h. The reaction mixture was cooled and dilutedwith water (75 mL). The resulting mixture was extracted with EtOAc. Theorganic layer was separated, dried (Na₂SO₄), filtered, and evaporated toyield a dark oil.

MH⁺251.1

Step C

A solution of the oil isolated in Step B (0.235 9) and zinc (3.06 g) inHOAc (25 mL) was stirred overnight. After overnight stirring, thereaction mixture was filtered through Dicalite. The filtrate wasevaporated to yield a residue. The residue was treated with 3N NaOH andCH₂Cl₂ with thorough mixing. The organic layer was separated, dried(Na₂SO₄), filtered, and evaporated to yield a thick residue.

MH⁺237.1

Step D

A solution of the residue isolated in Step C (0.240 g, 1.02 mmol) and2-nitro-5-phenoxybenzaldehyde (0.248 g, 1.02 mmol) in DCE (5.5 mL) wasstirred for 15 minutes. Then NaBH(OAc)₃ (0.300 g, 1.42 mmol) was added,and the reaction mixture was stirred overnight. To the reaction mixturewas added 3N NaOH and CH₂Cl₂ with thorough mixing. The layers wereseparated, and the organic layer was dried (Na₂SO₄), filtered, andevaporated to yield a thick oil.

MH⁺464.2

Step E

A solution of the oil isolated in Step D (0.500 g, 1.08 mmol) and 10%palladium on carbon (0.086 g) in EtOH (50 mL) was hydrogenated at 34 psion a Parr shaker. After 2 h, the reaction mixture was filtered andevaporated to yield a semisolid.

MH⁺434.2

Step F

To a solution of the semisolid (0.175 g, 0.4 mmol) prepared in Step E inEtOH (5 mL) was added cyanogen bromide (0.242 mL, 1.21 mmol) as a 5Msolution in MeCN. The reaction mixture was stirred over the weekend andthen evaporated to yield a residue. The residue was triturated severaltimes with diethyl ether and then filtered to yield a white solid. Ofthis material, 90 mg was purified on flash silica gel using 98:2 to90:10 CH₂Cl₂:(0.5MNH₃ in MeOH) to yield a residue. This residue wasdissolved in CH₂Cl₂, and TFA (0.5 mL) was added. The resulting solutionwas evaporated and triturated several times with diethyl ether to yieldthe title compound as a cream-colored solid.

MH⁺459.4

EXAMPLE 509-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-9H-fluorene-2-carboxylic acidcyclohexyl-methyl-amide (Compound #125)

Step A

A mixture of 9-oxo-9H-fluorene-2-carboxylic acid (0.448 g, 2.18 mmol),HBTU (0.826 g, 2.18 mmol), and N-ethylmorpholine (0.780 g, 6.76 mmol) inDMF (22 mL) was stirred for 30 minutes. Then N-methylcyclohexylamine(0.702 g, 6.22 mmol) was added, and the reaction mixture was stirred for3 h. With thorough mixing, 50 mL of 1 N HCl and EtOAc were added. Thelayers were separated, and the organic layer was washed with water andwith saturated aqueous NaCl solution and then again with water andaqueous NaCl solution. The organic layer was dried (Na₂SO₄), filteredand evaporated to yield a solid.

MH⁺319.9

Step B

A solution of the solid isolated in Step A (0.682 g, 3.13 mmol) andhydroxylamine (0.155 g, 4.70 mmol, 50% solution in water) in EtOH (24mL) was refluxed for 4 h. The reaction mixture was cooled and dilutedwith water (130 mL). The resulting mixture was extracted with EtOAc. Theorganic layer was separated, dried (Na₂SO₄), filtered, and evaporated toyield a solid.

MH⁺335.13

Step C

A solution of the solid isolated in Step B (0.562 g, 1.68 mmol) and zinc(5.47 g) in HOAc (30 mL) was stirred overnight. After overnightstirring, the reaction mixture was filtered through Filter Aid. Thefiltrate was evaporated to yield a residue. To the residue was added 3NNaOH (30 mL), and the resulting solution was extracted with diethylether. The diethyl ether extract was dried (Na₂SO₄), filtered, andevaporated to yield a thick light green residue.

MH⁺321.2

Step D

A solution of the residue isolated in Step C (0.378 g, 1.18 mmol) and2-nitro-5-phenoxybenzaldehyde (0.287 g, 1.18 mmol) in DCE (5 mL) wasstirred for 15 minutes. Then NaBH(OAc)₃ (0.380 g, 1.79 mmol) was added,and the reaction mixture was stirred overnight. To the reaction mixturewas added 3N NaOH and CH₂Cl₂ with thorough mixing. The layers wereseparated, and the organic layer was washed with saturated aqueous NaClsolution, dried (Na₂SO₄), filtered, and evaporated to yield a cleargreen oil.

MH⁺548.5

Step E

A solution of the oil isolated in Step D (0.707 g, 1.29 mmol) andstannous chloride monohydrate (1.60 g, 7.10 mmol) in EtOH (6 mL) wasrefluxed for 3 h. The resulting solution was cooled, and excess aqueoussodium bicarbonate solution and EtOAc were added, and the resultingmixture was filtered through Filter Aid. The organic layer wasseparated, dried (Na₂SO₄), filtered, and evaporated to yield a thickclear residue.

MH⁺518.3

Step F

To a solution of the residue (0.450 g, 0.87 mmol) prepared in Step E inEtOH (4 ML) was added cyanogen bromide (0.136 g, 1.29 mmol). Thereaction mixture was refluxed for 2.5 h. After cooling, the reactionmixture was evaporated to yield a thick dark residue. This residue wastriturated five times with diethyl ether. Filtration yielded a tansolid. Of this material, 0.200 g was purified on a Gilson HPLC to yieldthe title compound as a white solid.

MH⁺543.6

EXAMPLE 513-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-N-bicyclor2.2.1]hept-2-yl-3-cyclohexyl-propionamide(Compound #400)

Step A

A mixture of malonic acid (10.4 g, 0.1 mol), cyclohexane carboxaldehyde(11.2 g, 0.1 mol), and ammonium acetate (11.6 g, 0.15 mol) in EtOH (100mL) was refluxed overnight. The reaction was cooled to room temperature,and the product was collected as a white solid.

Step B

A solution of the solid isolated in Step A (1.4 g, 5.0 mmol),2-norbornylamine (0.6 g, 5.0 mmol), HBTU (1.9 g, 5.0 mmol), and TEA (0.5g, 5.0 mmol) in DMF was stirred for 3 days. The reaction mixture wasdiluted with water, and a precipitate formed. A white solid wascollected by filtration and allowed to air-dry overnight. The solid wasdissolved in CH₂Cl₂, dried (Na₂SO₄), and filtered. To the resultingsolution was added TFA (5 mL). The solvent was evaporated in vacuo toyield a residue which was dissolved in isopropanol. To this solution wasadded excess K₂CO₃. The suspension was filtered, and the filtrate wasconcentrated in vacuo to yield a yellow oil.

Step C

A solution of the oil isolated in Step B (1.1 g, 4.1 mmol) and2-nitro-5-phenoxybenzaldehyde (0.98 g, 4.0 mmol) in DCE (40 mL) wasstirred for 1 hour. Then NaBH(OAc)₃ (1.3 g, 6.0 mmol) was added, and thereaction mixture was stirred for three days. The reaction mixture wasquenched with 3N NaOH. The resulting solution was extracted with CH₂Cl₂.The CH₂Cl₂ extracts were combined, dried (K₂CO₃), and concentrated toyield a residue. Purification by flash chromatography 0 to 2% (1.0M NH₃in MeOH) in CH₂Cl₂ yielded a residue.

Step D

A solution of the residue isolated in Step C (0.15 g) and palladium oncarbon in EtOH was hydrogenated at 50 psi in a Parr shaker for 90minutes. The catalyst was removed by filtration, and the filtrate wasconcentrated under reduced pressure to a volume of 10 mL.

Step E

To the solution prepared in Step D was added cyanogen bromide (0.05 g,0.4 mmol). The reaction mixture was stirred at room temperatureovernight. The suspension was filtered to yield the title compound asolid.

MH⁺487

¹H NMR (300 MHz, DMSO-d₆): δ0.55-0.70 (br d, 0.5H), 0.75-0.85. (br d,0.5H), 0.90-1.82 (m, 20.5H), 1.98 (br d, J=14.7 Hz, 1H), 2.11 (br s,0.5H), 3.15-4.0 (br m, 2H), 4.10-4.25 (br m, 1H), 4.21-4.50 (m, 2H),6.93 (s, 1H), 6.95-7.05 (m, 4H), 7.15 (br t, J=7.2 Hz, 1H), 7.40 (t, 7.3Hz, 2 H), 7.78 (br s, 3H).

EXAMPLE 52 (R)-Enantiomer of cyclohexanecarboxylic acid[2-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-propyl]-amide (Compound #495)

Step A

A solution of L-alanamide (0.93 g, 7.5 mmol) and2-nitro-5-phenoxybenzaldehyde (1.2 g, 5.0 mmol) in THF was stirred for 1hour. Then NaBH(OAc)₃ (1.6 g, 7.5 mmol) was added, and the reactionmixture was stirred overnight. The reaction mixture was diluted withEtOAc and 3N NaOH. The layers were separated, and the EtOAc extract waswashed with brine, dried (K₂CO₃), and concentrated to a residue.Purification by flash chromatography 1.0 to 2.0% (0.5M NH₃ in MeOH) inCH₂Cl₂ yielded a residue.

Step B

To a solution of the residue (0.54 g, 1.7 mmol) isolated in Step B inTHF (20 mL) was added BH₃.THF (1.0M solution in THF, 7.6 mL), and themixture was heated at reflux overnight. After 24 h of heating,additional BH₃.THF (1.0M solution in THF, 5 mL) was added to thereaction mixture. After 16 h, the reaction mixture was cooled, and 1 NHCl was added. The resulting mixture was basified with Na₂CO₃ andextracted with EtOAc. The combined extracts were washed with brine,dried (K₂CO₃), filtered, and then evaporated in vacuo to yield an oil.Flash chromatography 2.5-7.5% (0.5N NH₃ in MeOH) in CH₂Cl₂ yielded anoil.

Step C

A solution of the oil isolated in Step B (0.27 g, 0.9 mmol) and TEA(0.125 mL, 0.9 mmol) in CH₂Cl₂ (5 mL) was cooled to 0° C. Then,cyclohexanecarbonyl chloride (0.13 g, 0.9 mmol) was added. The reactionmixture was warmed to room temperature and was stirred overnight.Additional cyclohexanecarbonyl (20 mL) chloride was added. The reactionmixture was stirred for 2 h. Then, 3N NaOH solution was added. Thelayers were separated, and the organic layer was dried (K₂CO₃),filtered, and evaporated in vacuo to yield a residue. Flashchromatography 5-25% (0.5N NH₃ in MeOH) in CH₂Cl₂ yielded a residue.

Step D

A solution of the residue isolated in Step C (0.25 g) and 10% palladiumon carbon in EtOH was hydrogenated at 50 psi in a Parr shaker for 3hours. The catalyst was removed by filtration, and the filtrate wasconcentrated under reduced pressure to a volume of 5 mL.

Step E

To the solution prepared in Step D was added cyanogen bromide (0.1 g).The reaction mixture was stirred at room temperature for 4 days. Thesolvent was evaporated to yield a residue which was divided into twoportions and purified by reversed phase HPLC using 30:70 MeCN:water with0.1% TFA as the eluent to yield the title compound as a white powder.

MH⁺407

¹H NMR (300 MHz, DMSO-d₆): δ0.98-1.38 (m, 6H), 1.20 (d, J=,6.5 Hz, 3 H),1.40-1.72 (m, 5H), 1.90-2.10 (br m, 1H), 3.08 (dt, J=4.8 Hz, 1H),4.12-4.32 (br m, 1H), 4.43 (s, 2H), 6.90 (s, 1H), 6.92-7.02 (m, 4H),7.13 (t, J=7.4 Hz, 1H), 7.38 (t, 7.6 Hz, 2 H), 7.38 (br t, 1H), 8.06 (brs, 2H)

EXAMPLE 53N-Adamantan-2-yl-3-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-propionamide(Compound #221)

Step A

To a solution of N-Boc β-alanine (4.7 g, 25.0 mmol), 2-adamantanaminehydrochloride (4.7 g, 25.0 mmol), and TEA (5.0 g, 50.0 mmol) in DMF (75mL) was added HBTU (9.5 g, 55.0 mmol). The reaction mixture was stirredovernight. The reaction mixture was diluted with water, and extractedwith EtOAc (2×). The organic layers were combined and washed with waterand brine and dried over K₂CO₃. Evaporation yielded a residue.

Step B

To a solution of the residue isolated in Step A (4.7 g, 25.0 mmol) inCH₂Cl₂ was added TFA (10 mL). The reaction mixture was concentrated to aresidue. To the residue was added EtOAc and water followed by solidNa₂CO₃. The layers were separated, and the aqueous layer was extractedtwice with EtOAc. The organic layers were combined, washed with brine,dried (K₂CO₃), filtered, and evaporated to yield a residue.

Step C

A solution of the residue isolated in Step B (0.55 g, 2.5 mmol) and2-nitro-5-phenoxybenzaldehyde (0.49 g, 2.0 mmol) in DCE was stirred for1 hour. Then NaBH(OAc)₃ (0.63 g, 3.0 mmol) was added, and the reactionmixture was stirred overnight. The reaction mixture was quenched with 3NNaOH. The resulting solution was extracted with CH₂Cl₂. The CH₂Cl₂extracts were combined, dried (K₂CO₃), and concentrated to a residue.Purification by flash chromatography 0.5 to 2.0% (0.5M NH₃ in MeOH) inCH₂Cl₂ yielded a residue.

Step D

A solution of the residue isolated in Step E (0.8 g) and 10% palladiumon carbon in EtOH was hydrogenated at 55 psi in a Parr shaker overnight.The catalyst was removed by filtration, and the filtrate wasconcentrated under reduced pressure to a volume of 20 mL.

Step E

To the solution prepared in Step D was added cyanogen bromide (0.26 g,2.5 mmol). The reaction mixture was stirred overnight. The reactionmixture was filtered to yield a white solid. The filtrate was evaporatedto yield a residue that was recrystallized from MeCN to yield a solidthat was combined with the collected solid from the reaction mixture.These were combined and recrystallized from CH₃CN to yield the titlecompound as a white solid.

MH⁺445

¹H NMR (300 MHz, DMSO-d₆): δ1.41 (d, J=12.2 Hz, 1H), 1.55-1.92 (m, 13H), 2.61 (t, J=6.0 Hz, 2H), 3.69 (t, J=5.5 Hz, 2H), 3.82 (d, J=6.6 Hz,1H), 4.55 (s, 2H), 6.67 (s, 1H), 6.90-7.05 (m, 4H), 7.13 (t, J=7.3 Hz,1H), 7.39 (t, 7.9 Hz, 2H), 7.96 (d, J=7.4 Hz, 1H), 8.00 (br s, 2H)

Elemental analysis for C₂₇H₃₂N₄O₂.1.0 HBr:

Calculated: C, 61.71; H, 6.33; N, 10.66.

Found: C, 61.77; H, 6.36; N, 10.57.

EXAMPLE 54N-Adamantan-2-yl-3-[2-amino-7-(2-methoxy-phenyl)-4H-quinazolin-3-yl]-propionamide(Compound #617)

Step A

To a solution of 4-bromo-2-nitrotoluene (2.16 g, 10.0 mmol) and2-methoxyphenyl boronic acid in EtOH (50 mL) was added K₂CO₃ (1.8 g,13.0 mmol) in water (1.8 mL) followed by Pd(dppf)Cl₂ (0.5 g, 0.065mmol). The reaction mixture was refluxed 4 h. The reaction mixture wascooled, filtered through Dicalite, and concentrated to yield a residue.The residue was purified by flash chromatography using 5% to 20% CH₂Cl₂in heptane to yield a yellow solid.

Step B

A mixture of the solid isolated in Step A (0.82 g, 3.4 mmol)dimethylformamide dimethyl acetal (0.6 mL, 4.4 mmol) in of DMF (4 mL)was heated for 2 h at 210° C. The mixture was cooled to roomtemperature, and the solvent was evaporated in vacuo to yield a residue.

Step C

The residue isolated in Step B was dissolved in THF (75 mL). The mixturewas diluted with water (75 mL) and NaIO₄ (4.3 g, 20.4 mol) was added.The reaction mixture was stirred overnight at room temperature. Thesolids were filtered and washed well with EtOAc. The filtrate was washed3× with saturated aqueous NaHCO₃ solution, and then dried (MgSO₄). Thesolution was filtered and the solvent was evaporated in vacuo. The crudeproduct was chromatographed to yield an off-white solid.

Step D

A solution of the solid isolated in Step C (0.32 g, 1.25 mmol), theresidue isolated in Example 53, Step B as its TFA salt (0.50 g, 1.5mmol), and TEA (1.25 mmol) in DCE was stirred for 1 h. Then NaBH(OAc)₃(0.33 g, 32.5 mmol) was added, and the reaction mixture was stirredovernight. The reaction mixture was quenched with 3N NaOH. The resultingsolution was extracted with CH₂Cl₂. The CH₂Cl₂ extracts were combined,dried (K₂CO₃), and concentrated to a residue. Purification by flashchromatography 1.0 to 2.5% (0.5M NH₃ in MeOH). in CH₂Cl₂ yielded ayellow glass.

Step E

A solution of the yellow glass isolated in Step D (0.24 g, 0.51 mmol)and 10% palladium on carbon in EtOH was hydrogenated at 55 psi in a Parrshaker for 3 h. The catalyst was removed by filtration, and the filtratewas concentrated under reduced pressure to a volume of 5 mL.

Step F

To the solution prepared in Step F was added cyanogen bromide (0.08 g,0.75 mmol). The reaction mixture was stirred overnight. The reactionmixture was filtered to yield a white solid. The filtrate was evaporatedto yield a residue that was purified by reversed phase HPLC (35% MeCN inH₂O with 0.1% TFA) to yield the title compound as a white powder.

MH⁺459

¹H NMR (300 MHz, DMSO-d₆): δ1.42 (d, J=12.7 Hz, 1H), 1.60-1.85 (m, 11H),1.88 (d, J=12.0 Hz, 2 H), 2.64 (br t, 2H), 3.65-3.80 (m, 2H), 3.76 (s,3H), 3.80-3.90 (m, 1H), 4.61 (s, 2H), 7.00-7.28 (m, 6H), 7.37 (t, 6.9Hz, 2 H), 7.97 (d, J=7.5 Hz, 1H), 8.03 (br s, 2H).

EXAMPLE 55 4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-heptanedioic acidbis-(cyclohexyl-methyl-amide) (Compound #84)

Step A

To a cold mixture of 4-ketopimelic acid (1.7415 g 10.0 mmol) andtriethylamine (7.00 mL, 50.2 mmol) in DMF (10 mL) was addeddiphenylphosphorylazide (5.1 mL, 23.7 mmol) and N-methylcyclohexylamine. The reaction mixture was stirred at ambient temperature 40 h. Thereaction was diluted with H₂O (50 mL) and extracted with EtOAc (2×100mL). The organic extracts were washed with water (4×50 mL), 1 N aqueousHCl (2×50 mL), H₂O (2×50 mL), dried (Na₂SO₄), filtered, and concentratedin vacuo to yield an oil. The crude oil was combined with productsynthesized previously on a 1 mmol scale and purified by flashchromatography on silica gel (2% MeOH in CHCl₃) to yield a residue.

MH⁺365

Step B

To a stirred solution of the residue isolated in Step A (1.1449 g, 3.14mmol) and ammonium acetate (2.4874 g, 32.3 mmol) in anhydrous methanol(30 mL) was added sodium cyanoborohydride (196.7 mg, 3.13 mmol). Theresulting mixture was stirred for 72 hours and then was treated with 1 Naqueous HCl to destroy excess borohydride reagent. The reaction mixturewas basified with 3N aqueous NaOH, and the aqueous mixture was extractedwith CHCl₃ (2×50 mL). The organic extracts were dried (Na₂SO₄),filtered, and concentrated to yield a colorless oil which was takenforward without further purification.

Step C

A mixture of 2-nitro-5-phenoxybenzaldehyde (760.2 mg, 3.13 mmol) and theoil isolated in Step B (1.1421 g, 3.12 mmol) in MeOH (30 mL) was stirredat room temperature for 2 days and then was cooled to 0° C. and treatedwith NaBH₄ (0.12 g, 3.17 mmol) and then stirred for another 20 h at roomtemperature. Aqueous NH₄Cl was added to destroy excess borohydridereagent. The aqueous mixture was extracted into CHCl₃ (2×50 mL). Theorganic solution was dried (Na₂SO₄), filtered, and concentrated in vacuoto yield a yellow oil. The crude oil was purified by columnchromatography (silica gel, 2% MeOH in CHCl₃) to yield a residue.

Step D

A heterogenous mixture of the oil isolated in Step C (162.5 mg, 0.27mmol), and 10% Pd/C (20 mg) in EtOH (25 mL) was shaken under 55 psi ofH₂ gas at room temperature for 20 h. The reaction mixture was filteredthrough a bed of Celite®, and the filter cake was rinsed with EtOH (25mL). The organic filtrate was evaporated. The residue was purified bypreparative TLC (2 tapered plates; 90:10:1 CHCl₃:MeOH:concentratedNH₄OH) to yield a yellow oil.

Step E

A mixture of the oil isolated in Step D (69.7 mg, 0.124 mmol) andcyanogen bromide (19.2 mg, 0.181 mmol) in EtOH (5 mL) was stirred atreflux for 6 h and then at room temperature for 60 h. The solvent wasremoved in vacuo, and remaining residue was triturated with Et₂O. Thesolvent was decanted and the remaining HBr salt was dried under highvacuum at room temperature overnight to yield the title compounds as atan amorphous solid.

MH⁺=588

¹H NMR (300 MHz, CDCl₃) 81.00-2.10 (m, 24H), 2.20-2.35 (m, 4H),2.60-2.80 (m, 6H), 3.30-3.45 (m, 1H), 4.10-4.25 (m, 3H), 4.30-4.45 (m,1H), 6.70 (s, 1H), 7.05-7.15 (m, 1H), 7.20-7.30 (m, 2H), 7.35-7.50 (m,2H), 11.5 (br s, 1H).

EXAMPLE 56 3-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-pentanedioic acidbis-(cyclohexyl-methyl-amide) (Compound #107)

Step A

To a cold (−60° C.) solution of 1,3-diamino-2-hydroxypropane (947.1 mg,10.0 mmol) and triethylamine (3.5 mL, 25.1 mmol) in a 4:1 THF:CH₂Cl₂mixture (50 mL) was added cyclohexanecarbonyl chloride (2.90 mL, 21.7mmol). The reaction was allowed to warm to room temperature over atwo-hour period. The heterogenous mixture was diluted with CH₂Cl₂ (20mL) and was stirred overnight. Thereafter, the mixture was washed withH₂O (50 mL), aqueous Na₂CO₃ (50 mL), and H₂O (50 mL), and then dried(Na₂SO₄), filtered, and concentrated to a residue. The residue waspurified by column chromatography (silica gel, 6% MeOH in CHCl₃) toyield a white solid.

Step B

To a stirred mixture of the solid isolated in Step A (2.1783 g, 7.03mmol) and triethylamine (10.0 mL, 71.7 mmol) in DMSO (20 mL) was addedsulfur trioxide pyridine complex (3.3662 g, 21.1 mmol) in DMSO (20 mL)under a N₂ atmosphere. The reaction mixture was stirred for 60 h andthen was diluted with ice water (100 mL) and extracted into CHCl₃ (2×75mL). The organic extracts were combined and washed with aqueous citricacid (2×125 mL), aqueous Na₂CO₃ (1×150 mL), H₂O (100 mL), dried(Na₂SO₄), filtered, and concentrated to yield an off-white solid.

Step C

To a solution of the solid isolated in Step B (924.2 mg. 3.00 mmol) inMeOH (40 mL) was added NH₄OAc (4.7890 g, 62.1 mmol). The mixture wasstirred at room temperature for 1 h and then was treated with NaBH₃CN(185.6 mg, 2.95 mmol). The reaction mixture was then stirred for 1 dayand then quenched with 1 N aqueous HCl solution (25 mL) and then wasbasified to pH 9.0 with Na₂CO₃ and extracted into CHCl₃ (2×50 mL). Theorganic solution was dried (Na₂SO₄), filtered, and concentrated. Theresidue was purified by column chromatography (silica gel, 8% MeOH inCHCl₃ to 90:10:1 CHCl₃:MeOH:concentrated NH₄OH) to yield an off-whitesolid.

Step D

A mixture of 5-phenoxy-2-nitrobenzaldehyde (217.1 mg, 0.893 mmol) andthe solid isolated in Step C (274.8 mg, 0.889 mmol) was stirred in MeOH(15 mL) at room temperature forl18 h. The resulting suspension wasdiluted with MeOH (5 mL), dissolved with gentle warming and treated withNaBH₄ (38.8 mg, 1.02 mmol). The reaction mixture was stirred for oneadditional hour and then quenched with aqueous NH₄Cl followed byextraction into CHCl₃ (2×50 mL). The organic solution was dried(Na₂SO₄), filtered, and evaporated to yield a residue that was carriedon to the next chemical step.

Step E

The residue isolated in Step D (274.5 mg) and 10% Pd/C (31.4 mg) inabsolute EtOH (30 mL) was shaken under 55 psi of H₂ at room temperaturefor 3 h. The reaction was filtered through a bed of Celite®, and thefilter cake was rinsed with solvent (50 mL). The organic filtrate wasevaporated and purified by preparative TLC (3 tapered silica gel plates,3 to 5% MeOH in CHCl₃) to yield a tan amorphous solid.

Step F

A mixture of the solid isolated in Step E (109.2 mg, 0.215 mmol) andBrCN (25.8 mg, 0.243 mmol) in EtOH (6 mL) was stirred at reflux for 18h. The solvent was removed in vacuo, and the remaining residue wastriturated with Et₂O. The solvent was decanted and the resulting HBrsalt was dried under high vacuum at room temperature overnight to yieldthe title compound as a tan amorphous solid.

MH⁺=532

¹H NMR (300 MHz, DMSO-d₆) 61.00-1.35 (m, 10H), 1.50-1.70 (m, 2H),1.90-2.10 (m, 2H), 3.15-3.25 (m, 2H), 3.45-3.55 (m, 2H), 4.25-4.35 (m,1H), 4.40 (s, 2H), 6.85 (s, 1H), 6.90-7.05 (m, 4H), 7.10-7.15 (m, 1H),7.35-7.45 (m, 2H), 7.75-7.80 (m, 2H), 7.85-7.95 (m, 2H), 10.5 (s, 1H)

EXAMPLE 575-[1-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-2-phenyl-ethyl]-oxazole-4-carboxylicacid cyclohexylamide (Compound #606)

Step A

To a cold (0° C.) mixture of DL-N-Cbz-phenylalanine (12.02 g, 40.0 mmol)and potassium carbonate sesquihydrate (26.50 g, 160 mmol) in anhydrousDMF was added diphenylphosphorylazide (13.5 mL, 62.6 mmol) and methylisocyanoacetate (7.5 mL, 82.5 mmol). The resulting mixture was stirredat room temperature for 96 h and then was diluted with H₂O (600 mL). Theprecipitated solid was collected by filtration. The crude solid wasdissolved in CHCl₃ (200 mL) and washed with aqueous NaCl. The organicsolution was dried (Na₂SO₄), filtered, and evaporated to yield a solid.The solid was carried on to the next step without further manipulation.

MH⁺=381

Step B

To a cold (0° C.) solution of the solid isolated in Step A (7.60 g, 20.0mmol) in 2:1 THF:H₂O (300 mL) was added LiOH (526.3 mg, 21.9 mmol). Themixture was stirred for 18 h, acidified to about pH 3 with aqueouscitric acid, and extracted into CHCl₃ (2×150 mL). The organic solutionwas dried (Na₂SO₄), filtered, and concentrated to yield a whiteamorphous solid that was carried on to the next step without furtherpurification.

Step C

To a cold (0° C.) mixture of the solid isolated in Step B (1.8339 g,5.00 mmol) and N,N-diisopropylethylamine (4.4 mL, 25.2 mmol) in DMF (12mL) was added diphenylphosphorylazide (1.3 mL, 6.03 mmol) andcyclohexylamine (0.74 mL, 6.47 mmol). The reaction mixture was stirredfor 20 h at room temperature and then was diluted with aqueous NaCl andextracted into CHCl₃ (2×100 mL). The organic solution was washed withH₂O (5×100 mL), dried (Na₂SO₄), filtered, and concentrated to a residue.The residue was purified by column chromatography (silica gel, 3% MeOHin CHCl₃). Trituration of the resulting gum with Et₂O yielded a whitesolid.

Step D

A mixture of the solid isolated in Step C (1.6532 g, 3.70 mmol) and 10%Pd/C (332.4 mg) in MeOH (120 mL) was shaken under 55 psi of hydrogen gasat room temperature for 5 h. The reaction mixture was filtered through abed of Celite®. The filter cake was rinsed with MeOH (50 mL). Thefiltrate was concentrated and the residue was purified by columnchromatography (silica gel, 6% MeOH in CHCl₃) to yield a light yellowoil.

Step E

To a solution of 5-phenoxy-2-nitrobenzaldehyde (267.0 mg, 1.10 mmol) andthe oil isolated in Step D (381.0 mg, 1.22 mmol) in 1,2-dichloroethanewas added sodium triacetoxyborohydride (362.1 mg, 1.71 mmol). Thereaction mixture was stirred at room temperature for 18 h and thenquenched with aqueous NaHCO₃ and extracted into CHCl₃ (2×40 mL). Theorganic solution was dried (Na₂SO₄), filtered, and concentrated. Theresidue was purified by column chromatography (silica gel, 3% MeOH inCHCl₃) to yield a light yellow gum.

Step F

A mixture of the gum isolated in Step E (532.6 mg, 0.970 mmol) and 10%Pd/C (110.4 mg) in EtOH (70 mL) was shaken under 55 psi of hydrogen gasat room temperature for 4 h. The reaction mixture was filtered through abed of Celite®. The filter cake was rinsed with MeOH (50 mL). Thefiltrate was concentrated and the residue was purified by columnchromatography (silica gel, 2% MeOH in CHCl₃) to yield a flaky brownsolid.

Step G

To a solution of the solid isolated in Step F (304.1 mg, 0.596 mmol) inEtOH (10 mL) was added cyanogen bromide (83.1 mg, 0.784 mmol). Theresulting mixture was stirred at room temperature for 1.5 d, refluxedfor 1 h, and then concentrated to a residue. The residue was purified bypreparative thin layer chromatography (5 tapered silica gel plates;90:10:1 CHCl₃:MeOH:concentrated NH₄OH) to yield the title compound as afree base.

The free base was dissolved in CHCl₃ (3 mL), acidified with 1 N HCl (0.6mL) in Et₂O and further diluted with Et₂O (75 mL). The HCl salt wascollected by filtration and dried under vacuum at room temperature toyield the title compound as an amorphous solid, as its HCl salt.

MH⁺=536

¹H NMR (300 MHz, DMSO-d₆) δ1.10-1.80 (m, 10H), 3.30-3.60 (m, 2H),3.65-3.85 (m, 1H), 4.25-4.35 (m, 1H), 5.05-5.15 (m, 1H), 5.90-6.10 (m,1H), 6.90-7.10 (m, 4H), 7.15-7.30 (m, 7H), 7.50-7.60 (m, 2H), 8.35-8.50(br s, 2H), 8.65-8.75 (m, 2H), 11.1 (s, 1H)

EXAMPLE 584-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-N-cyclohexyl-4-(cis-4-hydroxycyclohexyl)-N-methyl-butyramide(Compound #731)

Step A

Following the procedure described in PCT Publication WO 02/76450, a 500mL round bottom flask was charged with anhydrous MeOH (200 mL). Theflask was placed in an ice bath, cooled to 0° C., and treated withacetyl chloride (10 mL, 140 mmol) followed byD-(+)-4-hydroxyphenylglycine (10.01 g, 59.8 mmol). The reaction mixturewas stirred at room temperature for 18 h, then at 40° C. for 5 h andthen concentrated to an oil. The oil was redissolved in MeOH (250 mL)and the solution concentrated to yield a solid. The moist solid waswashed with Et₂O, dried in vacuum oven at 40° C. for 5 h to yield an offwhite solid. This material was carried on directly to the next step.

Step B

A suspension of D-(+)-4-hydroxyphenylglycine methyl ester (12.9620 g,59.8 mmol) in CH₂Cl₂ (150 mL) was treated with diisopropyl ether (15 mL,86.0 mmol), di-tert-butyl dicarbonate (15.1740 g, 69.5 mmol) in DCM (50mL) and N,N-diispropylethylamine (12.0 mL, 68.8 mmol). The resultingmixture was stirred for 60 h at room temperature and then wasconcentrated to a residue. The residue was dissolved in EtOAc (250 mL),washed with H₂O (2×100 mL), saturated NaHCO₃ (1×100mL), brine (1×100mL),dried (Na₂SO₄), filtered, and concentrated to a gummy residue. The gumwas triturated with 1:4 Et₂O: hexanes (200 mL) to yield a solid.

Step C

A solution of the solid (5.0550 g, 0.018 mol) isolated in Step B in HOAc(90 mL) was prepared with slight heating. Then PtO₂ (403.2 mg) wasadded, and the reaction was shaken under 50 psi of H₂ gas for 2 h atroom temperature. Acetic acid was evaporated by azeotropic removal usingbenzene as a cosolvent. The oily residue was diluted with EtOAc (100mL), washed with saturated aqueous NaHCO₃(100 mL), brine (100 mL) andH₂O (100 mL). The organic solution was dried (Na₂SO₄), filtered, andconcentrated to a thick oil which solidified upon standing. The solidwas purified by gradient column chromatography (silica gel; 10% to 60%EtOAc in heptane)on the Isco to yield the cis and trans isomers oftert-butoxycarbonylamino-(4-hydroxy-cyclohexyl)-acetic acid methyl esteras solids.

Step D

A mixture of the cis isomer isolated in Step C (998.0 mg, 3.48 mmol) andlithium hydroxide (179.5 mg, 7.49 mmol) in 70:33 THF:H₂O (103 mL) wasstirred at room temperature for 6 h. The reaction mixture was madeacidic by addition of citric acid (1.61 g), and then H₂O (25 mL) wasadded. The reaction mixture was extracted with CHCl₃ (2×75 mL). Theorganic solution was dried (Na₂SO₄), filtered, and concentrated to yielda foam which was carried on to the next chemical step without furtherpurification.

Step E

To a cooled (10° C.) suspension of the foam prepared in Step D (887.7mg, 3.25 mmol), N,O-dimethylhydroxylamine¹HCl (438.2 mg, 4.49 mmol) andN-hydroxybenzotriazole hydrate (607.9 mg, 4.50 mmol) in CH₂Cl₂ (30 mL)was added triethylamine (2.0 mL, 14.3 mmol) and1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide·HCl (866.2 mg, 4.52mmol). The reaction was allowed to warm to room temperature and then wasstirred overnight. The reaction mixture was diluted with CH₂Cl₂ (125mL), washed with brine (3×50 mL), aqueous citric acid (2×50 mL), dried(Na₂SO₄), filtered, and concentrated to a residue. The residue waspurified by column chromatography (silica gel; 7% MeOH in CHCl₃) toyield a residue.

Step F

To a cooled (0° C.) solution of the residue isolated in Step E (500.3mg, 1.58 mmol) in THF (22 mL) was added 1 M LiAlH₄ in THF (3.8 mL, 3.8mmol) in a dropwise manner over a 6 minute period. The resulting mixturewas stirred for 10 minutes at 0° C., then was allowed to warm to roomtemperature during a 20 minute interval and then was recooled in an icebath for 20 minutes. The cooled reaction mixture was treated with NaHSO₄(602.4 mg) in H₂O (10 mL) and aqueous citric acid (30 mL). The reactionmixture was extracted into EtOAc (2×50 mL), and the organic solution waswashed with H₂O (50 mL), dried (Na₂SO₄), filtered and concentrated toyield a crude residue, which was carried onto next step.

Step G

To an ice cold (0° C.) solution of trimethylphosphonoacetate (0.90 mL,6.24 mmol) in THF (20 mL) was added 60% NaH in mineral oil (unwashed;194.6 mg, 4.86 mmol) in three portions. The heterogeneous mixture wasfurther diluted with THF (10 mL) and was stirred at room temperature for2.5 h. The reaction mixture was cooled in ice bath for 15 minutes andthen was treated with the residue isolated in Step F (530.5 mg) in THF(30 mL). The ice bath was removed and the reaction mixture was allowedto warm to room temperature over a 45-minute interval. The reaction wasquenched with aqueous citric acid solution (50 mL) and extracted intoEtOAc (2×50 mL). The organic solution was dried (Na₂SO₄), filtered, andconcentrated. The residue was purified by column chromatography (silicagel; 70% EtOAc in heptane).to yield a white solid.

Step H

A heterogeneous mixture of the solid isolated in Step G (286.5 mg, 0.915mmol), and 10% Pd/C (72 mg) in MeOH (65 mL) was-shaken over 50 psi of H₂gas at room temperature for 4 h. The reaction mixture was filteredthrough a bed of Celite®, and the filter cake was rinsed with CHCl₃/MeOH(50 mL). The organic filtrate was concentrated to yield a solid. Thereaction was repeated with additional solid prepared as in Step G (177.4mg) to yield additional solid product. Both batches were combined andcarried onto the next step without further manipulation.

Step I

A mixture of the compound isolated in Step H (400.0 mg, 1.27 mmol) andlithium hydroxide (65.8 mg, 2.75 mmol) in 7:3 THF:H₂O (40 mL) wasstirred for 3 h and then was allowed to stand at room temperature for 20h. The reaction mixture was treated with citric acid (764.2 mg, 3.98mmol) and water (25 ml) and then was stirred for 15 minutes and then wasextracted into CHCl₃ (3×50mL). The organic solution was washed with H₂O(50 mL), dried (Na₂SO₄), filtered and concentrated to yield a whitesolid.

Step J

To a cooled (10° C.) suspension of the solid isolated in Step 1(331.6mg, 1.10 mmol), triethylamine (0.21 mL, 1.50 mmol) andN-hydroxybenzotriazole hydrate (204.6 mg, 1.51 mmol) in DMF (10 mL) wasadded N-methyl-cyclohexylamine (0.20 mL, 1.52 mmol), triethylamine (0.29mL, 2.08 mmol) and 1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide,HCl(289.3 mg, 1.51 mmol). After the reaction stirred at 0° C. for 1 h, theice bath was removed, and the reaction was allowed to warm to roomtemperature and then was stirred for an additional 18 h. The reactionmixture was diluted with CHCl₃ (75 mL), washed with H₂O (4×75 mL), dried(Na₂SO₄), filtered, and concentrated to a residue. The residue waspurified by column chromatography (silica gel; 6% MeOH in CHCl₃) toyield a residue.

Step K

A solution of the residue isolated in Step J (382.4 mg, 0.966 mmol) inCH₂Cl₂ (15 mL) was treated with trifluoroacetic acid (3 mL) and stirredfor 2 h at room temperature. The reaction mixture was concentrated togive a residue, which was basified with aqueous NaHCO₃, extracted intoCHCl₃ (12×40 mL). The organic extracts were dried (Na₂SO₄), filtered,and evaporated to yield an oil.

Step L

A mixture of 2-nitro-5-phenoxybenzaldehyde (189.9 mg, 0.781 mmol) andthe oil isolated in Step K (231.2 mg, 0.781 mmol) in MeOH (15 mL) wasstirred at room temperature for 40 h and then was cooled in an ice bathfor 30 minutes. The reaction mixture was treated with NaBH₄ (65.5 mg,1.73 mmol) and was stirred for 1 h at room temperature. The reaction wasquenched with aqueous NH₄Cl (50 mL) and then was extracted into CHCl₃(2×50 mL). The organic solution was dried (Na₂SO₄), filtered, andconcentrated. The residue was purified by column chromatography (silicagel, 6% MeOH in CHCl₃) to yield a yellow gum.

Step M

A heterogenous mixture of the yellow gum (345.7 mg, 0.660 mmol) isolatedin Step L and 10% Pd/C (74.5 mg) in EtOH (70 mL) was shaken over 53 psiof H₂ gas at room temperature for 4 h. The reaction mixture was filteredthrough a bed of Celite®, and the filter cake was rinsed with EtOH (50mL). The organic filtrate was concentrated to a yellow flaky solid thatwas carried onto the next step without further manipulation.

Step N

To a solution of the solid isolated in Step M (290.2 mg, 0.5886 mmol) inEtOH (10 mL) was added 3M cyanogen bromide in CH₂Cl₂ (200 μL, 0.600mmol) at room temperature. The resulting mixture was stirred at roomtemperature for 20 h, and then was treated with additional cyanogenbromide solution (25 μL) and was heated at 55° C. for 4 h. The reactionmixture was concentrated to a residue that was purified by preparativeTLC (4 tapered silica gel plates; 80:18:2 CHCl₃:MeOH:NH₄OH) to yield thetitle compound as a beige solid as its free base.

A solution of the free base (135.0 mg) in CHCl₃ (3 mL) was acidifiedwith 1 N HCl (0.5 mL) in Et₂O and was further diluted with Et₂O (75 mL).The HCl salt was collected by filtration and dried in the vacuum oven at50° C. to yield the title compound a residue, as a 6:4 mixture ofrotamers, as HCl salt.

MH⁺=519

¹H NMR (300 MHz, DMSO-d₆) δ1.00-2.10 (m, 21H), 2.15-2.25 (m, 1H),2.40-2.60 (m, 1H), 2.75 (s, 0.4×1H), 2.85 (s, 0.6×1H), 3.40-3.50 (m,1H), 4.00 (br s, 1H), 4.20-4.45 (m, 4H), 6.65 (s, 1H), 6.80-6.90 (m,3H), 7.10-7.15 (m, 1H), 7.20-7.25 (m, 1H), 7.35-7.40 (m, 2H), 8.25 (brs, 2H), 11.70-11.75 (m, 1H)

EXMAPLE 59 (S)-enantiomer of4-cis-{[4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4-cyclohexyl-butyryl]-methyl-amino}-cyclohexanecarboxylicacid (Compound #739)

Step A

To a stirred solution of cis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (7.19 g, 29.6 mmole) in THF (100 mL) at 0° C., lithiumaluminum hydride pellets (6.73 g, 177 mmole) were added slowly. Afterthe addition of lithium aluminum hydride, the solution was stirred atroom temperature for 2 h. Then, the solution was heated at refluxovernight. After cooling to room temperature, potassium sodium tartratetetrahydrate and water were added to terminate the reaction. Thesolution was filtered through a pad of Celite®. Ethanol was used to washthe pad. The filtrate was evaporated, and the residue was dissolved in6N hydrochloric acid (50 mL). The solution was concentrated to yield acolorless oil which was used directly in the next step without furtherpurification.

MH⁺=144.0

Step B

To a stirred solution of the (S)-enantiomer of4-tert-butoxycarbonylamino-4-cyclohexyl-butyric acid (prepared as inExample 28, Step E) (10.07 g, 35.3 mmole), the oil isolated in Step A(9.51 g, 52.9 mmole), and DIPEA (18.5 mL, 106.2 mmole) in DMF (100 mL),HBTU (9.51 g, 25.1 mmole) was added. After stirring at room temperatureovernight, the solution was diluted with diethyl ether (300 mL). Thesolution was extracted with 1 N HCl (80 mL) three times, and once withwater, and dried over magnesium sulfate. The solution was concentratedto yield a colorless oil.

MH⁺=411.1

Step C

A stirred mixture of the oil isolated in Step B (13.20 g, 32.1 mmole) inaqueous 15% sodium bicarbonate solution (150 mL), sodium bromide (0.661g, 6.4 mmole), and TEMPO (0.1005 g, 6.4 mmole) in acetone (400 mL) wascooled to 0° C., and trichloroisocyanuric acid (14.94 g, 64.3 mmole) wasadded slowly over 30 min. The solution then was warmed to roomtemperature and was stirred at this temperature for 24 hours. Thesolution was filtered through Celite®. The organic solvent wasevaporated. Sodium carbonate (5.0 g) was added. The solution was washedwith ethyl acetate once and then was acidified with 1 N HCl. Theresulting solution was extracted with ethyl acetate three times. Thecombined organic extracts were dried over magnesium sulfate. The solventwas evaporated to yield a colorless oil.

MH⁺=425.3

Step D

To a stirred solution of the oil isolated in Step C (7.4 g, 17.4 mmole)in dichloromethane (100 mL), trifluoroacetic acid (100 mL) was added.The solution was stirred at room temperature for 1 hour and then wasconcentrated. Water (50 mL) was added. Sodium bicarbonate was addeduntil there was no bubbling from the solution. The resulting mixture wasextracted with ethyl acetate three times. The combined organic phaseswere dried over magnesium sulfate. The solvent was evaporated to yield awhite solid which was used directly in the next reaction.

Step E

To a stirred solution of the solid isolated in Step D in dichloromethane(100 mL), 2-nitro-5-phenoxy-benzaldehyde (3.85 g, 15.8 mmole), aceticacid (4.0 mL) and 4A molecular sieves (5.0 g) were added. After stirringat room temperature for 20 min, the solution was cooled to 0° C., andsodium triacetoxyborohydride (3.36 g, 15.8 mmole) was added slowly intothe solution. The solution was stirred at this temperature for 7-8hours, and then was allowed to warm up overnight. The solution wasfiltered through a pad of Celite®. The filtrate was concentrated. Theresidue was treated with 1 N HCl (30 mL). The solution was extractedwith ethyl acetate twice. The combined organic phases were washed withaqueous 1 N NaOH solution twice. The combined aqueous extracts wereacidified by adding 1 N HCl. The solution was extracted with ethylacetate twice. The combined organic phases was dried over magnesiumsulfate. The solvent was evaporated to yield a slightly colored solid.

MH⁺=552.3

Step F

To a solution of the solid isolated in Step E (2.80 g, 3.6 mmole) in asolvent mixture of THF (40 mL) and ethanol (60 mL), 10% palladium oncarbon (1.24 g) was added. The solution was subjected to hydrogenationfor 1 hour at 30 psi. The solution was filtered through a pad of Celite®to yield a solution.

Step G

To the solution obtained in Step F, cyanogen bromide (3M indichloromethane, 2.5 mL, 7.6 mmole) was added. The solution was stirredat room temperature overnight and then was concentrated. Water (100 mL)was added. Sodium bicarbonate was added until no more bubbling wasobserved. The solution was extracted with ethyl acetate twice. Thecombined organic phases were dried over magnesium sulfate. Afterremoving the solvent, the residue was purified over silica gel columneluted with a mixture of dichloromethane and methanol from 99:1 to 70:30to yield the title compound as a white solid.

MH⁺=547.5

¹H NMR (300 MHz, DMSO), δ0.83-2.27 (m, 24H), 2.54 (s, 3H), 3.32 (s, 2H),3.79 (m, 1H), 4.35-4.41 (m, 3H), 6.95-7.16 (m, 6H), 7.35-7.41 (m, 2H),8.04 (br s, 1H)

EXAMPLE 60 (S)-Enantiomer of4-cis-{[4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4-(tetrahydro-pyran-4-yl)-butyryl]-methyl-amino}-cyclohexanecarboxylicacid (Compound #745)

Step A

A stirred solution of the oil isolated in Example 59, Step A (6.69 g,27.5 mmole) in 15% aqueous sodium bicarbonate solution (80 mL), sodiumbromide (0.566 g, 5.5 mmole), and TEMPO (0.0859 g, 5.5 mmole) in acetone(200 mL) was cooled to 0° C., and trichloroisocyanuric acid (12.78 g,55.0 mmole) was added slowly over 30 min. The reaction mixture then waswarmed to room temperature and was stirred at this temperature for 24hours and then was filtered through Celite®. The organic solvent wasevaporated. Sodium carbonate (5.0 g) was added. The solution was washedwith ethyl acetate once and then was acidified with 1 N HCl. Theresulting solution was extracted with ethyl acetate three times. Thecombined organic extracts were dried over magnesium sulfate. The solventwas evaporated to yield a white solid.

MH⁻=256.1

Step B

Acetyl chloride (4.0 mL, 55 mmole) was added slowly to methanol at 0°C., and the mixture was stirred at this temperature for 30 min. Thesolid isolated in Step A (7.31 g, 28.4 mmole) was added. The solutionwas warmed to room temperature. After stirring at room temperature for 1hour, the solution was heated at reflux overnight. The solvent wasevaporated. The residue was recrystallized from acetone and diethylether to yield a white solid.

MH⁺=172.2

Step C

To a stirred solution of the (S)-enantiomer of4-tert-butoxycarbonylamino-4-(tetrahydro-pyran-4-yl)-butyric acid(Example 32, Step I) (0.74 g, 2.57 mmole), the solid isolated in Step B(0.59 g, 2.84 mmole), and DIPEA (1.8 mL, 10.3 mmole) in DMF (10 mL),HBTU (1.27 g, 3.3 mmole) was added. After stirring at room temperatureovernight, the solution was diluted with diethyl ether (50 mL). Thesolution was washed with 1 N HCl (20 mL) three times and once withwater, and dried over magnesium sulfate. The solution was concentratedto yield a slightly colored oil.

MH⁺=441.2

Step D

To a stirred solution of the oil isolated in Step C (1.23 g, 2.8 mmole)in dichloromethane (25 mL), trifluoroacetic acid (25 mL) was added. Thesolution was stirred at room temperature for 2 hours and then wasconcentrated. Water (50 mL) was added. Sodium bicarbonate was addeduntil there was no bubbling from the solution. The resulting mixture wasextracted with ethyl acetate three times. The combined organic phaseswere dried over magnesium sulfate. The solvent was evaporated to yield ablack oil. Step E

To a stirred solution of the solid isolated in Step D (0.28 g, 1.15mmole) in dichloromethane (10 mL), 2-nitro-5-phenoxy-benzaldehyde (0.39g, 1.15 mmole), acetic acid (0.2 mL), and 4 Å molecular sieves (0.9 g)were added. After stirring at room temperature for 1 hour, the solutionwas cooled to 0° C., and sodium triacetoxyborohydride was added slowlyinto the solution. The solution was stirred at this temperature for 8hours and then was allowed to warm up overnight. The solution wasfiltered through a pad of Celite®, and the filtrate was concentrated.The residue was dissolved in ethyl acetate, and the solution was washedwith aqueous 1 N NaOH solution twice and once with water and then wasdried over magnesium sulfate. The solvent was evaporated to yield aslightly colored solid.

MH⁺=568

Step F

To a solution of the solid isolated in Step E (0.47 g, 0.83 mmole) inethanol (50 mL), 10% palladium on carbon (0.37 g) was added. The mixturewas subjected to hydrogenation for 1 hour at 30 psi. The reactionmixture was filtered through a pad of Celite® to yield a solution.

Step G

To the solution obtained in Step F, cyanogen bromide (3M indichloromethane, 0.42 mL, 1.26 mmole) was added. The solution wasstirred at room temperature overnight and then was concentrated. Theresidue was purified on HPLC to yield a white solid as its TFA salt.

MH⁺=563.2

Step H

To a stirred solution of the solid isolated in Step G (0.045 g, 0.066mmole) in a solvent mixture of THF (1.0 mL), methanol (1.0 mL), andwater (1.0 mL), aqueous 1 N NaOH (0.6 mL) was added. The solution wasstirred at room temperature for 58 hours. The reaction mixture wasneutralized with 1 N HCl and then was purified by HPLC to yield thetitle compound as a white solid as its TFA salt.

MH⁺=549.3

¹H NMR (300 MHz, DMSO), δ1.30-2.27 (m, 18H), 2.55 (m, 4H), 3.24 (m, 2H),3.88 (m, 3H), 4.39-4.45 (m, 2H), 6.96-7.04 (m, 5H), 7.11-7.16 (m, 1H),7.36-7.39 (m, 2H), 7.93 (s, 2H), 10.76 (s, 1H), 12.1 (s, 1H).

EXAMPLE 61 (S)-Enantiomer of4-cis-[[4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4-cyclohexyl-butyryl]-(2-hydroxy-ethyl)-amino]-cyclohexanecarboxylicacid (Compound #749)

Step A

A solution of cis-4-aminocyclohexanecarboxylic acid HCl salt (10.27 g,71.7 mmole), benzyl alcohol (36.4 mL, 351.7 mmole), andp-toluenesulfonic acid monohydrate (16.37 g, 86.0 mmole) in toluene (500mL) was refluxed in a round bottom flask fitted with a condenser andDean-Stark trap for 24 hours. Then the reaction mixture was cooled to 0°C., and diethyl ether was added. A white precipitate was produced andwas collected by filtration. The precipitate was dissolved in ethylacetate (400 mL). The organic solution was washed with aqueous sodiumcarbonate solution three times and saturated aqueous sodium chlorideonce and then dried over magnesium sulfate. The solvent was removed toyield a colorless oil.

MH⁺=234.0

Step B

To a stirred solution of the oil isolated in Step A (6.25 g, 26.8 mmole)in methanol (100 mL) was added benzyloxyacetaldehyde (3.76 mL, 26.8mmole). After stirring at room temperature for one hour, the solutionwas cooled to 0° C. Sodium borohydride (1.01 g, 26.7 mmole) was addedslowly to the solution. After the solution was stirred at 0° C. for onehour, 2N HCl (30 mL) was added. The solution was washed with diethylether twice and then was basified by adding solid sodium carbonate. Theaqueous phase was extracted with ethyl acetate twice. The combinedorganic phases were washed with saturated sodium bicarbonate twice andsaturated sodium chloride once and then was dried over magnesiumsulfate. The solvent was removed to yield a colorless oil.

MH⁺=368.3

Step C

To a stirred solution of the (S)-enantiomer of4-tert-butoxycarbonylamino-4-cyclohexyl-butyric acid (prepared as inExample 28, Step E) (2.67 g, 10.3 mmole), the oil isolated in Step B(3.78 g, 10.3 mmole), and DIPEA (3.3 mL, 34.5 mmole) in DMF (50 mL),HBTU (4.61 g, 12.1 mmole) was added. After stirring at room temperatureovernight, the solution was diluted with diethyl ether (200 mL). Thesolution was extracted with 1 N HCl (20 mL) three times and once withwater and dried over magnesium sulfate. This material was purified on asilica gel column with 10:90 to 60:40 ethyl acetate:heptane to yield acolorless oil.

MH⁺=635.4

Step D

To a stirred solution of the oil isolated in Step C (4.34 g, 6.8 mmole)in dichloromethane (20 mL), trifluoroacetic acid (20 mL) was added. Thesolution was stirred at room temperature for 2 hours and then wasconcentrated. Water (50 mL) was added. Sodium bicarbonate was addeduntil there was no more bubbling from the solution. The resultingmixture was extracted with ethyl acetate three times. The combinedorganic phases were dried over magnesium sulfate. The solvent wasevaporated to yield a colorless oil which was used directly in the nextreaction.

Step E

To a solution of the solid isolated in Step D in ethanol (60 mL), 10%palladium on carbon (1.2 g) was added. The solution was subjected tohydrogenation for 4 hours at 50 psi. The solution was filtered through apad of Celite® to yield a white solid.

MH⁺=355.2

Step F

To a stirred solution of the solid isolated in Step E (0.47 g, 1.3mmole) and 2-nitro-5-phenoxy-benzaldehyde (0.29 g, 1.2 mmole) indichloromethane (40 mL), acetic acid (0.2 mL) and 4A molecular sieves(1.0 g) were added. After stirring at room temperature for 30 min, thesolution was cooled to 0° C., and sodium triacetoxyborohydride (0.51 g,2.4 mmole) was added slowly into the solution. The solution was stirredat this temperature for 8 hours, and then was allowed to warm upovernight. The filtrate was concentrated, and the residue was treatedwith ethyl acetate (100 mL). The solution was filtered through a pad ofCelite®. The filtrate was washed with saturated aqueous sodiumbicarbonate solution three times and once with brine and then was driedover magnesium sulfate. The solvent was evaporated to yield a colorlessoil.

MH⁺=582.3

Step G

To a solution of the solid isolated in Step F (1.36 g, 2.3 mmole) in asolvent mixture of THF (10 mL) and ethanol (60 mL), 10% palladium oncarbon (1.4 g) was added. The solution was subjected to hydrogenationfor 30 minutes at 30 psi. The solution was filtered through a pad ofCelite® to yield a solution. The solvent was removed, and the residuewas dissolved in ethyl acetate. The solution was extracted withsaturated sodium bicarbonate solution twice and dried over magnesiumsulfate. The solvent was removed to yield a residue that was useddirectly in the next step.

Step H

To the residue obtained in Step G, cyanogen bromide (3M indichloromethane, 0.42 mL, 1.26 mmole) was added. The solution wasstirred at room temperature overnight and then was concentrated. Theresidue was purified by HPLC to yield the title compound as a whitesolid, as its TFA salt.

MH⁺=577.3

¹H NMR (300 MHz, DMSO), δ1.30-2.49 (m, 25H), 3.28 (m, 2H), 3.30 (m, 3H),3.82 (m, 1H), 4.34-4.49 (m, 2H), 6.97-7.07 (m, 5H), 7.14-7.16 (m, 1H),7.36-7.40 (m, 2H), 7.93 (s, 2H), 10.77 (s, 1H), 12.1 (s, 1H)

EXAMPLE 62 (S)-Enantiomer of4-cis-[[4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4-(tetrahydro-pyran-4-yl)-butyryl]-(2-hydroxy-ethyl)-amino]-cyclohexanecarboxylicacid (Compound #750)

Step A

To an ice cooled solution of (S)-enantiomer of4-tert-butoxycarbonylamino-4-(tetrahydro-pyran-4-yl)-butyric acid (2.4g, 8 mmol), prepared as in Example 32, Step I,cis-4-(2-benzyloxyethylamino)cyclohexanecarboxylic acid benzyl ester(3.0 g, 8.1 mmol), prepared by as in Example 61, Step B, HOBT (1.4 g, 10mmol) in CH₂Cl₂ (100 mL), TEA (2.3 mL, 16 mmol) was added followed by1,3-dimethylamino propyl-3-ethylcarbodiimide (2.0 g, 10 mmol). Themixture was allowed to warm to room temperature and then was stirredovernight. Then, EtOAc (200 mL) was added, and this solution was washedwith citric acid solution, NaHCO₃ solution, and NaCl solution. Theorganic layer was separated, dried with MgSO₄, and evaporated to yieldan oil. The crude product (oil) was purified by column chromatography(1:1 hexane:EtOAc) to yield a colorless oil.

MH⁺637.3

Step B

A solution of the colorless oil isolated in Step A (4.8 g, 7.5 mmol) in5% TFA:CH₂Cl₂ (100 mL) was stirred at room temperature overnight. Anadditional 2 mL of TFA was added, and the solution was stirred at roomtemperature for another hour. The solvent and most of TFA was evaporatedto yield a residue. To the residue was added EtOAc (300 mL). Theresulting solution was washed with aqueous NaHCO₃ and NaCl solutions.The organic layer was separated, dried with MgSO₄, and evaporated toyield a light brown oil.

MH⁺537.2

Step C

A solution of the oil isolated in Step B (1.9 g, 3.5 mmol),2-nitro-5-phenoxybenzaldehyde (0.86 g, 3.5 mmol) in 1,2-dichloroethane(100 mL) was stirred at room temperature for 4 h. Then, NaBH(OAc)₃ (1.3g, 6.1 mmol) was added, and the reaction mixture was stirred at roomtemperature overnight. The solution was poured into saturated NaHCO₃solution and then was extracted with EtOAc (2×200 mL). The organic layerwas dried with MgSO₄ and evaporated. Column chromatography (1:1heptane:EtOAc) yielded a yellow oil.

MH⁺764.1

Step D

To a solution of the oil isolated in Step C (1.45 g, 1.9 mmol) in MeOH(250 mL), zinc dust (16.7 g) and NH₄C1 (2.0 g, 38 mmol) were added. Theresulting mixture was refluxed for 4 h. The residual zinc was removed byfiltration through Celite®. After the MeOH was removed, EtOAc (300 mL)was added, the solution was washed with aqueous NaHCO₃ and NaClsolutions. The organic layer was dried with MgSO₄ and evaporated toyield a light brown oil.

MH⁺734.4

Step E

A solution of the oil isolated in Step D (0.67 g, 0.9 mmol) and BrCN (3Min CH₂Cl₂, 0.31 mL, 0.93 mmol) in EtOH (20 mL) was stirred at roomtemperature overnight. The EtOH was evaporated to yield a crude residue,as its HBr salt, which was used directly in next reaction.

MH⁺759.9

Step F

A solution of the residue isolated in Step E (0.35 g, 0.42 mmol) and 10%Pd on carbon (0.18 g) in EtOH (100 mL) was subjected to hydrogenation at10 psi for 48 h. The reaction mixture then was filtered through Celite®,and the filtrate was concentrated to yield a residue. Purification byHPLC yielded the title compound as a residue, as its TFA salt.

MH⁺579.1

¹H NMR (300 MHz, CD₃OD): δ0.91-1.25 (m, 4H), 1.51-1.76 (m, 10H),2.02-2.21 (m, 8H), 3.3-3.61 (m, 8H), 3.9-3.99 (m, 2H), 4.05-4.15 (m,2H), 6.74 (s, 1H), 6.95 (d, J=7.84 Hz, 2H), 6.99-7.06 (m, 2H), 7.11 (m,1H), 7.35 (m, 2H).

In addition to the desired title compound, HPLC separation yielded the(S)-enantiomer of4-[[4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4-(tetrahydro-pyran-4-yl)-butyryl]-(2-benzyloxy-ethyl)-amino]-cyclohexanecarboxylicacid (Compound #751):

MH⁺669.2, MH⁻667.4

¹H NMR (300 MHz, CD₃OD): δ1.17-1-33 (m, 4H), 1.46-1.68 (m, 6H),1.76-1.89 (m, 4H), 2.18-2.27 (m, 2H), 2.6-2.8 (m, 6H), 3.13-3.29 (m,2H), 3.43-3.54 (m, 1H), 3.53-3.54 (d, J=5.16 Hz, 2H), 3.94-4.02 (m, 1H),4.06 (d, J=5.16 Hz, 2H), 4.46 (s, 2H), 6.68 (d, J=2.33 Hz, 1H), 6.94 (d,J=7.03 Hz, 2H), 7.10-7.21 (m, 2H), 7.28-7.3 (m, 8H).

EXAMPLE 63 (S)-4-tert-Butoxycarbonylamino-5-methyl-hexanoic acid(Smrcina, M., Majer, P., Majerová, E., Guerassina, T. A., Eissenstat, M.A., Tetrahedron, 1997, 53 (38), 12867)

Step A:(R)-[1-(2,2-Dimethyl-4,6-dioxo-[1,3]dioxane-5-carbonyl)-2-methyl-propyl]-carbamicacid, tert-butyl ester

A 5 L four-necked flask (equipped with mechanical stirrer, nitrogeninlet, thermocouple, and glass stopper) was charged with Boc-D-Valine(143.6 g, 0.661 mol) and dichloromethane (2.8 L). The reaction waschilled to −3° C. in an ice bath, and then 4-N,N-dimethylaminopyridine(124.6 g, 1.02 mol) and Meldrum's acid (104.8 g, 0.727 mol) were addedto the reaction. To the reaction mixture was then added1-[3-(dimethylaminopropyl)]-3-ethylcarbodiimide hydrochloride (EDCl,139.4 g, 0.727 mol) over a five-minute period, and then the reactionmixture was allowed to warm to room temperature over 18 h (overnight).The reaction mixture was washed with 5% (w/w) aqueous potassiumbisulfate (4×600 mL), dried (MgSO₄), and the solution was used directlyin the next step without concentration or purification. A small portionwas concentrated and displayed the following analytical data.

Mass Spectrum (Electrospray, Negative mode): m/z=342 (M−1).

HPLC: R_(t)=5.051 min; ABZ+PLUS, 3 μm, 2.1×50 mm

Gradient: A=water (0.1% TFA), B=ACN (0.1% TFA) @ 0.75 mL/min

-   -   Initial: A:B, 90:10.t=0.00-4.00 min (A:B, 10:90), t=4.00-4.10        min (A:B, 0:100), t=4.10-6.00 min (A:B, 0:100)

Step B:(S)-[1-(2,2-Dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl)-2-methyl-propyl]-carbamicacid, tert-butyl ester

In a 5 L one-neck flask four-necked flask (equipped with mechanicalstirrer, nitrogen inlet, thermocouple, and glass stopper), was chargedthe solution of(R)-[1-(2,2-dimethyl-4,6-dioxo-[1,3]dioxane-5-carbonyl)-2-methyl-propyl]-carbamicacid, tert-butyl ester in dichloromethane prepared in Step A above,(˜3.2 L). The reaction was chilled to ˜3° C. in an ice bath, and aceticacid was added (437 g, 7.27 mol). The reaction mixture was then treatedwith sodium borohydride granules (62.5 g, 1.65 mol), which were added inportions over 1 h. During the addition the reaction temperatureincreased to ˜9° C. and was stirred at that temperature 1.5 h and thenwas split into two portions. Each portion was poured into brine (1 L),stirred (magnetically) for 20 minutes, and partitioned. Each organicphase was washed with brine (3×750 mL) and distilled water (2×500 mL).The combined organic phases were dried (MgSO₄) and concentrated to yieldcrude product. The crude product was dissolved inheptane-dichloromethane (˜1:1) and loaded onto a Biotage 150M cartridge(2.5 kg silica gel) and then eluted with heptane (2 L), 15:85 (14 L),3:7 (16 L), and 1:1 ethyl acetate-heptane (8 L) to give two mainfractions. The first fraction yielded the desired material contaminatedwith minor impurities.

Melting Point: 108-112° C.

Optical Rotation: [α]_(D)=−10.2° (c 4.15, MeOH, 23° C.)

The second fraction yielded additional product, which displayed thefollowing analytical data.

Melting Point: 115-117° C.

Optical Rotation: [α]_(D)=−11.2° (c 4.18, MeOH, 23° C.)

Mass Spectrum (Electrospray, Negative mode): m/z=328 (M−1)

HPLC: R_(t)=3.700 min; ABZ+PLUS, 3 μm, 2.1×50 mm

Gradient: A=water (0.1% TFA), B=ACN (0.1% TFA) @ 0.75 mL/min

-   -   Initial: A:B, 90:10.t=0.00-4.00 min (A:B, 10:90), t=4.00-4.10        min (A:B, 0:100), t=4.10-6.00 min (A:B, 0:100)

Step C: (S)-2-Isopropyl-5-oxo-pyrrolidine-1-carboxylic acid, tert-butylester

In a 3 L, one-necked flask (equipped with a magnetic stir bar and acondenser with nitrogen inlet) was charged(S)-[1-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl)-2-methyl-propyl]-carbamicacid, tert-butyl ester prepared in Step B above (147 g, 0.446 mol) andtoluene (1.4 L). The reaction mixture was heated to reflux for 4 h thencooled to room temperature and concentrated in vacuo to yield crudeproduct as a residual oil. The crude product was dissolved in heptane(˜200 mL) and loaded onto a Biotage 75 L (800 g silica gel) and elutedwith heptanes (1 L), 1:9 (7 L), and 1:3 ethyl acetate-heptane (2 L) toyield the product as an oil.

Optical Rotation: [α]_(D)=−71.9° (c 1.05, CHCl₃, 23° C.);

-   -   lit value (R) +77.4° (c 1.4, CHCl₃)

Optical Rotation: [α]_(D)=−72.2° (c 0.983, MeOH, 23° C.)

Elemental Analysis: C₁₂H₂₁NO₃:

Calculated: % C=63.41, % H=9.31, % N=6.16

Found: % C=63.51, % H=9.35, % N=6.41

Step D: (S)-4-tert-Butoxycarbonylamino-5-methyl-hexanoic acid

A 2 L, one-necked flask (equipped with a magnetic stir bar and anitrogen inlet) was charged with(S)-2-isopropyl-5-oxo-pyrrolidine-1-carboxylic acid, tert-butyl esterprepared in Step C above (77.4 g, 0.341 mol) and acetone (260 mL). Tothis solution was added 1 M aqueous sodium hydroxide (408 mL, 0.408mol), and the reaction mixture was stirred 30 minutes. The acetone wasremoved in vacuo and the resulting aqueous slurry was acidified, withvigorous stirring, by addition of solid sodium bisulfate (55 g, 0.45mol) and diluted to 1 L with deionized water. The slurry was stirred for2 h and the resulting white solid was collected by filtration, washedwith deionized water, and dried in a vacuum oven to yield the product asa white solid.

Melting Point: 107-109° C.

Optical rotation: [α]_(D)=−6.40° (c 4.13, MeOH, 23° C.);

-   -   lit value (R) +2.9° (c 1.4, EtOH)

Mass Spectrum (Electrospray, Positive mode): m/z=267.9 (M⁺Na)

Elemental Analysis: C₁₂H₂₃NO₄:

Calculated: % C=58.75, % H=9.45, % N=5.71

Found: % C=58.84, % H=9.21, % N=5.60

The opposite enantiomer was prepared in an identical fashion startingfrom Boc-L-Valine and gave the following analytical data.

Melting Point: 91-95° C.

Optical rotation: [α]_(D)=+5.49° (c 3.16, MeOH, 23° C.)

Mass Spectrum (Electrospray, Positive mode): m/z=268.0 (M+Na)

Karl Fisher Titration: 0.20% (w/w); indicated 0.3 mol eq. hydrate.

Elemental Analysis: C₁₂H₂₃NO₄.0.3 H₂O:

Calculated: % C=57.49, % H=9.49, % N=5.59

Found: % C=57.78, % H=10.04, % N=5.21

EXAMPLE 64 (S)-4-tert-Butoxycarbonylamino-5-methyl-hexanoic acid, benzylester

A 50 mL, one-neck round bottom flask (equipped with a magnetic stirrerand a nitrogen inlet) was charged with(S)-4-tert-butoxycarbonylamino-5-methyl-hexanoic acid prepared as inExample 63 above (500 mg, 2.04 mmol), cesium carbonate (1.99 g, 6.11mmol), benzyl chloride (773 mg, 6.11 mmol), and tetrahydrofuran (15 mL).The reaction was stirred at room temperature for three days (weekend)and then was heated to a mild reflux for 6 h. The reaction mixture waspoured into saturated aqueous sodium bicarbonate (100 mL) and extractedwith ethyl ether (2×100 mL). The combined organics were dried andconcentrated to give 1 g of crude product. The residue was dissolved inheptane-dichloromethane (9:1, ˜7 mL) and eluted through a 12 g Iscosilica gel cartridge to yield the title compound as a solid.

Melting Point: 94-96° C.

Optical rotation: [α]_(D)=−8.52° (c 4.08, MeOH, 23° C.)

Mass Spectrum (Electrospray, Positive mode): m/z=357.9 (M+Na)

Elemental Analysis: C₁₉H₂₉NO₄:

Calculated: % C=68.03, % H=8.71, % N=4.18

Found: % C=68.06, % H=8.97, % N=4.07

HPLC: R_(t)=4.157 min; ABZ+PLUS, 3 μm, 2.1×50 mm

Gradient: A=water (0.1% TFA), B=ACN (0.1% TFA) @ 0.75 mL/min.

Initial: A:B, 90:10

-   -   t=0.00-4.00 min (A:B, 10:90), t=4.00-4.10 min (A:B, 0:100),        t=4.10-6.00 min (A:B, 0:100)

Chiral HPLC: R_(t)=5.865 min; Chiralpak AD, 10 μm, 4.6×250 mm

Isocratic: Hexane:Iso-Propanol (9:1)

The small amount of the enantiomer was synthesized as a reference andhad the following characteristics (19415-84A).

Melting Point: 94-96° C.

Mass Spectrum (Electrospray, Positive mode): m/z=357.9 (M+Na)

HPLC: R_(t)=4.208 min; ABZ+PLUS, 3 μm, 2.1×50 mm

Gradient: A=water (0.1% TFA), B=ACN (0.1% TFA) @ 0.75 mL/min

Initial: A:B, 90:10

-   -   t=0.00-4.00 min (A:B, 10:90), t=4.00-4.10 min (A:B, 0:100),        t=4.10-6.00 min (A:B, 0:100)

Chiral HPLC: R_(t)=11.376 min; Chiralpak AD, 10 μm, 4.6×250 mm.

Isocratic: Hexane:Iso-Propanol (9:1)

Evaluation of the chiral HPLC indicated an enantiomeric excess of −97.3%for each isomer. This indicates that there is little to no racemizationin this synthetic route.

EXAMPLE 65 3-(3-Dimethoxymethyl-4-nitro-phenoxy)-phenylamine

3-Aminophenol (0.050 mol) was dissolved in DMA (100 mL). K₂CO₃ (0.060mol) was added. 4-Chloro-2-dimethoxymethyl-1-nitrobenzene (0.050 mol)was added, and the reaction mixture was stirred overnight at 100° C. andthen for 2 hours at 120° C. The reaction mixture was poured into waterand this mixture was extracted with diisopropyl ether. The separatedorganic layer was dried, filtered and the solvent evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂:CH₃OH 100:0 (to remove unreacted4-chloro-2-dimethoxymethyl-1-nitrobenzene) up to 70:30). The desiredfractions were collected and the solvent was evaporated to yield aresidue.

EXAMPLE 66N-[3-(3-Dimethoxymethyl-4-nitro-phenoxy)-phenyl]-benzenesulfonamide

A mixture of 3-(3-dimethoxymethyl-4-nitro-phenoxy)phenylamine (0.013mol) in THF (100 mL) and TEA (200 mL) was stirred at room temperatureand a mixture of benzenesulfonyl chloride (0.013 mol) in THF (50 mL) wasadded dropwise, then the reaction mixture was stirred overnight at roomtemperature and again overnight at 60° C. The solvent was evaporated andthe residue was stirred in H₂O. After extraction with CH₂Cl₂, theorganic layer was separated, dried, filtered off and the solvent wasevaporated. The residue was purified by Biotage column chromatography(eluent: CH₂Cl₂ 100%). The purest product fractions were collected andthe solvent was evaporated to yield the title compound as a residue.

EXAMPLE 67 N-[3-(3-Formyl-4-nitro-phenoxy)-phenyl]-benzenesulfonamide

A mixture ofN-[3-(3-dimethoxymethyl-4-nitrophenoxy)-phenyl]-benzenesulfonamide(0.0083 mol) in THF (12 mL) was stirred at room temperature, then 12NHCl (6 mL) and water (6 mL) were added and the reaction mixture wasstirred for 48 hours at room temperature. The mixture was stirred in H₂Oand extracted with diisopropyl ether. The organic layer was separated,washed with a 10% NaHCO₃ solution, separated again, dried, filtered, andthe solvent was evaporated. The obtained residue was stirred indiisopropyl ether, and then the desired product was filtered off anddried to yield the title compound as a solid.

EXAMPLE 68N-[3-(4-Nitro-3-propylaminomethyl-phenoxy)-phenyl]-benzenesulfonamide

Under N₂, a mixture ofN-[3-(3-formyl-4-nitrophenoxy)-phenyl]-benzenesulfonamide (0.0060 mol)and propylamine (0.0085 mol) in DCE (50 mL) was stirred at roomtemperature, then NaBH(OAc)₃ (0.0080 mol) was added and the reactionmixture was stirred overnight at room temperature. A saturated NaHCO₃solution (50 mL) was added and the layers were separated. The organiclayer was dried, filtered off and the solvent was evaporated. Theresidue was purified over silica gel filter (eluent: 98:2 CH₂Cl₂:CH₃OH).The purest product fractions were collected and the solvent wasevaporated to yield the title compound as a residue.

EXAMPLE 69N-[3-(4-Amino-3-propylaminomethyl-phenoxy)-phenyl]-benzenesulfonamide

A mixture ofN-[3-(4-nitro-3-propylaminomethyl-phenoxy)-phenyl]-benzenesulfonamide(0.0045 mol) in methanol (100 mL) was hydrogenated with 10% Pd/C (0.5 g)as a catalyst in the presence of thiophene solution (1 mL). After uptakeof H₂ gas (3 equiv.), the reaction mixture was filtered over Dicaliteand the filtrate was evaporated to yield the title compound as aresidue.

EXAMPLE 70N-[3-(2-Amino-3-propyl-3,4-dihydro-quinazolin-6-yloxy)-phenyl]-benzenesulfonamide

A mixture ofN-[3-(4-amino-3-propylaminomethyl-phenoxy)-phenyl]-benzenesulfonamide(0.0044 mol) in ethanol (50 mL) was stirred at room temperature andcyanogen bromide (0.0064 mol) was added, then the reaction mixture wasstirred and refluxed for 4 hours. After cooling, the precipitate wasfiltered off and was stirred in boiling CH₃CN with CH₃OH. The resultingsolids were filtered off, washed with diisopropyl ether and dried toyield the title compound as a solid.

EXAMPLE 71 3-(3-Dimethoxymethyl-4-nitrophenoxy)-benzonitrile

A mixture of 3-hydroxybenzonitrile (0.129 mol) in N,N-dimethyl-acetamide(200 mL) was stirred at room temperature and K₂CO₃ (0.147 mol) wasadded, then 4-chloro-2-dimethoxymethyl-1-nitrobenzene (0.086 mol) wasadded and the reaction mixture was stirred for 24 hours at 130° C. Thesolvent was evaporated and the residue was stirred in H₂O. Afterextraction with CH₂Cl₂, the organic layer was separated, dried, filteredoff and the solvent was evaporated. The residue was purified over asilica gel filter (eluent: CH₂Cl₂ 100%). The purest product fractionswere collected and the solvent was evaporated to yield the titlecompound as residue.

EXAMPLE 72 3-(3-Formyl-4-nitrophenoxy)-benzonitrile

A mixture of 3-(3-dimethoxymethyl-4-nitro-phenoxy)-benzonitrile (0.068mol) in water (55 mL) was stirred at room temperature, and then 12N HCl(55 mL) and THF (140 mL) were added, and the reaction mixture wasstirred overnight at room temperature. The mixture was stirred in H₂Oand extracted with diisopropyl ether. The organic layer was separated,washed with a 10% NaHCO₃ solution, separated again, dried, filtered offand the solvent was evaporated. The obtained residue was stirred indiisopropyl ether, and then the desired product was filtered off anddried to yield the title compound as a solid.

EXAMPLE 73 3-(4-Nitro-3-propylaminomethyl-phenoxy)-benzonitrile

Under N₂, a mixture of 3-(3-formyl-4-nitrophenoxy)-benzonitrile (0.056mol) and propylamine (0.059 mol) in DCE (450 mL) was stirred at roomtemperature, and then NaBH(OAc)₃ (0.063 mol) was added, and the reactionmixture was stirred overnight at room temperature. A saturated NaHCO₃solution was added, and the layers were separated. The organic layer wasdried, filtered off and the solvent was evaporated. The residue waspurified over silica gel filter (eluent: 99:1 CH₂Cl₂:CH₃OH). The purestproduct fractions were collected and the solvent was evaporated to yieldthe title compound as a residue.

EXAMPLE 74 3-(4-Amino-3-propylaminomethyl-phenoxy)-benzonitrile

A mixture of 3-(4-nitro-3-propylaminomethyl-phenoxy)-benzonitrile (0.045mol) in methanol (250 mL) was hydrogenated with 10% Pd/C (2 g) as acatalyst in the presence of thiophene solution (2 mL). After uptake ofH₂ gas (3 equiv.), the reaction mixture was filtered over Dicalite andthe filtrate was evaporated. The residue was purified by columnchromatography over silica gel (eluent: 98:2 CH₂Cl₂:CH₃OH). The purestproduct fractions were collected and the solvent was evaporated to yieldthe title compound as a residue.

EXAMPLE 753-(2-Amino-3-propyl-3,4-dihydro-quinazolin-6-yloxy)-benzonitrile

A mixture of 3-(4-amino-3-propylaminomethyl-phenoxy)-benzonitrile (0.032mol) in ethanol (400 mL) was stirred at room temperature, and cyanogenbromide (0.038 mol) was added, and then the reaction mixture was stirredand refluxed for 2 hours. After cooling, the precipitate was filteredoff, washed with diisopropyl ether and dried to yield crude product as asolid.

The filtrate was evaporated and the obtained residue was crystallizedfrom CH₃CN:diisopropyl ether, then the precipitate was filtered off,washed with diisopropyl ether, and dried to yield an additional crop ofthe title compound as a solid.

EXAMPLE 76[6-(3-Cyano-phenoxy)-3-propyl-3,4-dihydro-quinazolin-2-yl]-carbamic acidtert-butyl ester

A mixture of3-(2-amino-3-propyl-3,4-dihydro-quinazolin-6-yloxy)-benzonitrile (0.021mol) and TEA (2.5 g) in THF (400 mL) was stirred at 5° C., thent-butoxycarbonyl anhydride (0.023 mol) was added, and the reactionmixture was stirred over the weekend at room temperature. The solventwas evaporated, then the residue was stirred in H₂O and the mixture wasextracted with CH₂Cl₂. The organic layer was separated, dried, filteredoff and the solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: 99:1 CH₂Cl₂:CH₃OH). The purestproduct fractions were collected and the solvent was evaporated to yieldthe title compound as residue.

EXAMPLE 77[6-(3-Aminomethyl-phenoxy)-3-propyl-3,4-dihydro-quinazolin-2-yl]-carbamicacid tert-butyl ester

A mixture of[6-(3-cyano-phenoxy)-3-propyl-3,4-dihydro-quinazolin-2-yl]-carbamic acidtert-butyl ester (0.0197 mol) in a solution of ammonia in methanol (250mL) was hydrogenated at 14° C. with Raney nickel (1 g) as a catalyst.After uptake of H₂ gas (2 equiv.), the reaction mixture was filteredover Dicalite and the filtrate was evaporated to yield the titlecompound as a residue.

EXAMPLE 78(3-Propyl-6-{3-[(2,4,6-trimethyl-benzylamino)-methyl]-phenoxy}-3,4-dihydro-quinazolin-2-yl)-carbamicacid tert-butyl ester

Under N₂, a mixture of[6-(3-aminomethyl-phenoxy)-3-propyl-3,4-dihydro-quinazolin-2-yl]-carbamicacid tert-butyl ester (0.0007 mol) and 2,4,6-trimethyl-benzaldehyde(0.0007 mol) in DCE (10 mL) was stirred at room temperature, thenNaBH(OAc)₃ (0.2 g) was added, and the reaction mixture was stirredovernight at room temperature. A saturated NaHCO₃ solution was added,and the layers were separated. The organic layer was dried, filtered offand the solvent was evaporated. The residue was purified by Biotagecolumn chromatography (gradient eluent: CH₂Cl₂:CH₃OH). The purestproduct fractions were collected and the solvent was evaporated to yieldthe title compound as a residue.

EXAMPLE 793-Propyl-6-{3-[(2,4,6-trimethyl-benzylamino)-methyl]-phenoxy}-3,4-dihydro-quinazolin-2-ylamine

A mixture of(3-propyl-6-{3-[(2,4,6-trimethyl-benzylamino)-methyl]-phenoxy}-3,4-dihydro-quinazolin-2-yl)-carbamicacid tert-butyl ester (0.00041 mol) in trifluoroacetic acid (1 mL) andDCM (10 mL) was stirred overnight at room temperature and the solventwas evaporated. The obtained residue was decomposed in diisopropylether/CH₃CN, then the desired product was filtered off and dried toyield the title compound as a solid.

mp 184.5° C.

EXAMPLE 80 3-(3-Dimethoxymethyl-4-nitro-phenylsulfanyl)-phenylamine

K₂CO₃ (0.085 mol) was added to a mixture of 3-aminothiophenol (0.075mol) in DMA (150 mL), then 4-chloro-2-dimethoxymethyl-1-nitrobenzene(0.050 mol) was added and the reaction mixture was stirred for 2 hoursat 80° C. H₂O was added and the mixture was extracted with diisopropylether. The crude product was purified by column chromatography (eluent:70:30 CH₂Cl₂:hexane up to 99:1 CH₂Cl₂:CH₃OH). The product fractions werecollected and the solvent was evaporated to yield the title compound asa residue which contained about 10% of an impurity. (The product wasused in subsequent steps without further purification.)

EXAMPLE 81N-[r3-(3-Dimethoxymethyl-4-nitro-phenylsulfanyl)-phenyl]-benzenesulfonamide

A mixture of 3-(3-dimethoxymethyl-4-nitro-phenylsulfanyl)-phenylamine(0.0384 mol) and TEA (0.0576 mol) in THF (q.s.) was stirred at 5° C.,and benzenesulfonyl chloride (0.0384 mol) was added dropwise at 5° C.,then the reaction mixture was reacted at room temperature and purifiedby column chromatography over silica gel (eluent: CH₂Cl₂). The productfractions were collected and the solvent was evaporated to yield thetitle compound as a residue. (The product was used in subsequent stepswithout further purification.)

EXAMPLE 82N-[3-(3-Formyl-4-nitro-phenylsulfanyl)-phenyl]-benzenesulfonamide

A mixture ofN-[3-(3-dimethoxymethyl-4-nitro-phenylsulfanyl)-phenyl]-benzenesulfonamide(0.027 mol) in 12N HCl (25 mL), THF (75 mL) and water (50 mL) wasstirred overnight at room temperature, and then the mixture wasextracted with ethyl acetate. The extract was washed with water and witha saturated aqueous Na₂CO₃ solution. The solvent was evaporated and theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂). The product fractions were collected and the solvent evaporatedto yield the title compound as a residue.

EXAMPLE 83N-[3-(4-Nitro-3-propylaminomethyl-phenylsulfanyl)-phenyl]-benzenesulfonamide

A mixture ofN-[3-(3-formyl-4-nitro-phenylsulfanyl)-phenyl]-benzenesulfonamide(0.0027 mol), propylamine (0.003 mol) and NaBH(OAc)₃ (0.0041 mol) in DCE(60 mL) was reacted overnight at room temperature. Then a 10% NaOHsolution was added and the mixture was extracted with CH₂Cl₂. Theextract was dried (MgSO₄) and then purified by column chromatographyover silica gel (eluent: 1:0 to 7:1 CH₂Cl₂:CH₃OH). The product fractionswere collected and the solvent was evaporated to yield the titlecompound as a residue.

EXAMPLE 84N-[3-(4-Amino-3-propylaminomethyl-phenylsulfanyl)-phenyl]-benzenesulfonamide

A mixture ofN-[3-(4-nitro-3-propylaminomethyl-phenylsulfanyl)-phenyl]-benzenesulfonamide(0.0016 mol) in methanol (50 mL) was hydrogenated with 10% Pd/C (0.1 g)as a catalyst. After uptake of H₂ gas (3 equiv.), the catalyst wasfiltered off and the filtrate was evaporated to yield the title compoundas a residue. (The product was used in subsequent steps without furtherpurification.)

EXAMPLE 85N-[3-(2-Amino-3-propyl-3,4-dihydro-quinazolin-6-ylsulfanyl)-phenyl]-benzenesulfonamide

A mixture ofN-[3-(4-Amino-3-propylaminomethyl-phenylsulfanyl)-phenyl]-benzenesulfonamide(0.0016 mol) and cyanogen bromide (0.0020 mol) in ethanol (q.s.) wasreacted overnight at room temperature and then the organic solvent(EtOH) was evaporated. The obtained concentrate was warmed in EtOH andthen cooled. The mixture was filtered and the collected residue wasrecrystallized from EtOH to yield the title compound as a solid.

mp 196.8-274° C.

EXAMPLE 86 N-[2-(2-Bromo-phenyl)-ethyl]-benzenesulfonamide

Benzenesulfonyl chloride (0.011 mol) was slowly added dropwise at roomtemperature to a mixture of 2-bromophenylethylamine (0.01 mol) and TEA(0.013 mol) in THF (50 mL). Then the reaction mixture was stirredovernight at room temperature, and the solvent was evaporated. Theobtained residue was washed with H₂O and extracted with CH₂Cl₂. Theorganic layer was separated, dried (MgSO₄), filtered off and the solventwas evaporated. The residue was stirred in diethyl ether, then thedesired product was filtered off and dried (vac.) to yield the titlecompound as an oil.

EXAMPLE 872-Nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde

A mixture of Pd₂(dba)₃ (0.0007 mol) and tricyclohexylphosphine (0.0029mol) in dry dioxane (200 mL) was stirred under N₂ for 30 min,and then2-nitro-4-bromobenzaldehyde (0.040 mol), pinacol diborane(4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane) (0.044mol), and potassium acetate (0.060 mol) were added and the reactionmixture was stirred for 16 hours under N₂ at 80° C. The mixture wascooled to room temperature and the solvent was evaporated. The obtainedresidue was washed with H₂O and extracted with CH₂Cl₂. The organic layerwas separated, dried (MgSO₄), filtered off and the solvent wasevaporated. The residue was purified by short column chromatography oversilica gel (eluent: 100% CH₂Cl₂). The purest product fractions werecollected and the solvent was evaporated. The residue was stirred inhexane, and then the resulting precipitate was filtered off and dried toyield the title compound as a residue.

EXAMPLE 88N-[2-(3′-Formyl-4′-nitro-biphenyl-2-yl)-ethyl]-benzenesulfonamide

A mixture of2-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde(0.001 mol), N-[2-(2-bromo-phenyl)-ethyl]-benzenesulfonamide (0.0012mol) and Pd(PCy₃)₂Cl₂ (0.00005 mol) in DME (5 mL) and 1M Na₂CO₃ (2 mL)in a reaction vial was stirred for 3 hours at 80° C., then DME wasremoved under a stream of N₂ and the resulting mixture was extractedwith CH₂Cl₂. The mixture was filtered through Extrelut, and the organiclayer was blown dry, then the desired product was isolated byFAST-synthesis to yield the title compound as a residue.

EXAMPLE 89N-[2-(4′-Nitro-3′-propylaminomethyl-biphenyl-2-yl)-ethyl]-benzenesulfonamide

NaBH(OAc)₃ (0.0031 mol) was added to a mixture ofN-[2-(3′-formyl-4′-nitro-biphenyl-2-yl)-ethyl]-benzenesulfonamide(0.0021 mol) and propylamine (0.0023 mol) in DCE (2 mL), and thereaction mixture was stirred overnight under N₂. The excess ofNaBH(OAc)₃ was decomposed with CH₃OH, and the solvent was evaporated.The residue was purified by Biotage column chromatography (eluent: 95:5CH₂Cl₂:CH₃OH). The purest product fractions were collected and then thesolvent was evaporated and co-evaporated with toluene to yield the titlecompound as a residue.

EXAMPLE 90N-[2-(4′-Amino-3′-propylaminomethyl-biphenyl-2-yl)-ethyl]-benzenesulfonamide

A mixture ofN-[2-(4′-nitro-3′-propylaminomethyl-biphenyl-2-yl)-ethyl]-benzenesulfonamide(0.00031 mol) in methanol (50 mL) was hydrogenated with 10% Pd/C (0.100g) as a catalyst in the presence of thiophene solution (0.5 mL). Afteruptake of H₂ gas (3 equiv.), the reaction mixture was filtered overDicalite and the filtrate was evaporated to yield the title compound asa residue. (The compound was used without further purification,immediately in the next reaction step.)

EXAMPLE 91N-{2-[2-(2-Amino-3-propyl-3,4-dihydro-quinazolin-6-yl)-phenyl]-ethyl}-benzenesulfonamide

Cyanogen bromide (0.00034 mol) was added to a mixture ofN-[2-(4′-amino-3′-propylaminomethyl-biphenyl-2-yl)-ethyl]-benzenesulfonamide(0.00031 mol) in ethanol (1 mL) in a Fast-tube, and then the reactionmixture was stirred overnight at room temperature. The solvent wasevaporated and the residue was purified by high-performance liquidchromatography. The purest product fractions were collected and thesolvent was evaporated to yield the title compound as a residue.

EXAMPLE 92 [3-(3-Dimethoxymethyl-4-nitro-phenoxy)-phenyl]-carbamic acidbenzyl ester

A mixture of 3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenylamine (0.14mol), prepared as in Example 65, and diisopropyl ether (0.16 mol) in DCM(1000 mL) was cooled to 10° C., and carbonochloridic acid phenylmethylester (also known as benzyl chloroformate) (0.16 mol) was addeddropwise, then the reaction mixture was stirred overnight at roomtemperature and washed with H₂O. The organic layer was separated, dried(MgSO₄), filtered off and the solvent was evaporated. The residue waspurified by column chromatography (eluent: 100% CH₂Cl₂). The productfractions were collected and the solvent was evaporated to yield thetitle compound as a residue.

EXAMPLE 93 [3-(3-Formyl-4-nitro-phenoxy)-phenyl]-carbamic acid benzylester

12N HCl (33 mL) and water (66 mL) were added to a mixture of[3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenyl]-carbamic acid benzylester (0.14 mol) in THF (400 mL) and the reaction mixture was stirredfor 48 hours at room temperature. The mixture was diluted with H₂O (500mL) and extracted 2 times with diisopropyl ether. The organic layer wasseparated, dried (MgSO₄), filtered off and the solvent was evaporated.The resulting product was removed with a spatula and dried under vacuumto yield the title compound as a residue.

EXAMPLE 94 [3-(4-Nitro-3-propylaminomethyl-phenoxy)-phenyl]-carbamicacid benzyl ester

A mixture of [3-(3-formyl-4-nitro-phenoxy)-phenyl]-carbamic acid benzylester (0.038 mol) in DCE (300 mL) was cooled in an ice bath to 15° C.,then propylamine (0.042 mol), followed by NaBH(OAc)₃ (0.057 mol) whichwas added portionwise. The reaction mixture was stirred overnight atroom temperature and the mixture was washed with a saturated NaHCO₃solution. The organic layer was separated, dried (MgSO₄), filtered offand the solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: 90:10 CH₂Cl₂:CH₃OH). The productfractions were collected and the solvent was evaporated, thenco-evaporated with toluene to yield the title compound as a residue.

EXAMPLE 95 [3-(4-Amino-3-propylaminomethyl-phenoxy)-phenyl]-carbamicacid benzyl ester

A mixture of [3-(4-nitro-3-propylaminomethyl-phenoxy)-phenyl]-carbamicacid benzyl ester (0.033 mol) in THF (200 mL) was hydrogenated with 10%Pt/C (2 g) as a catalyst in the presence of thiophene solution (2 mL).After uptake of H₂ gas (3 equiv.), the reaction mixture was filteredthrough Dicalite, and the filtrate was evaporated. The residue waspurified by column chromatography (eluent: 90:10 CH₂Cl₂:(CH₃OH:NH₃)).The product fractions were collected, and the solvent was evaporated toyield the title compound as an oil.

EXAMPLE 96[3-(2-Amino-3-propyl-3,4-dihydro-quinazolin-6-yloxy)-phenyl]-carbamicacid benzyl ester

A mixture of [3-(4-Amino-3-propylaminomethyl-phenoxy)-phenyl]-carbamicacid benzyl ester (0.032 mol) and cyanogen bromide (0.035 mol) inethanol (250 mL) was stirred and refluxed for 2 hours, then the reactionmixture was cooled to room temperature and the solvent was evaporated.The residue was converted into its free base with a NaOH solution andthe resulting mixture was extracted with CH₂Cl₂. The organic layer wasseparated and the solvent was evaporated, then the residue was stirredin diisopropyl ether, filtered off and dried under vacuum to yield thetitle compound as a solid.

EXAMPLE 97[6-(3-Benzyloxycarbonylamino-phenoxy)-3-propyl-3,4-dihydro-quinazolin-2-yl]-carbamicacid tert-butyl ester

A mixture of[3-(2-amino-3-propyl-3,4-dihydro-quinazolin-6-yloxy)-phenyl]-carbamicacid benzyl ester (0.011 mol) in DCM (100 mL) was cooled to 5° C. Then,a solution of t-butoxycarbonyl anhydride (0.013 mol) in DCM (20 mL) wasadded dropwise, and the reaction mixture was stirred overnight at roomtemperature. Extra t-butoxycarbonyl anhydride (q.s.) was added and theresulting mixture was stirred for 3 hours at 30° C. The solvent wasevaporated and the obtained residue was stirred in diisopropyl ether.Finally, the resulting precipitate was filtered off and dried undervacuum to yield the title compound as a solid.

EXAMPLE 98[6-(3-Amino-phenoxy)-3-propyl-3,4-dihydro-quinazolin-2-yl]-carbamic acidtert-butyl ester

A mixture of[6-(3-benzyloxycarbonylamino-phenoxy)-3-propyl-3,4-dihydro-quinazolin-2-yl]-carbamicacid tert-butyl ester (0.008 mol) in methanol (150 mL) was hydrogenatedwith 10% Pd/C (1 g) as a catalyst. After uptake of H₂ gas (1 equiv.),the reaction mixture was filtered over Dicalite and the filtrate wasevaporated. The residue was stirred in diisopropyl ether and theresulting precipitate was filtered off and dried to yield the titlecompound as a solid.

EXAMPLE 99{3-Propyl-6-[3-(2,4,6-trimethyl-benzylamino)-phenoxy]-3,4-dihydro-quinazolin-2-yl}-carbamicacid tert-butyl ester

2,4,6-Trimethyl-benzaldehyde (0.0005 mol) was added to a mixture of[6-(3-amino-phenoxy)-3-propyl-3,4-dihydro-quinazolin-2-yl]-carbamic acidtert-butyl ester (0.0005 mol) in DCE (3 mL) and the mixture was stirredfor 5 min. at room temperature, and then NaBH(OAc)₃ (0.0006 mol) wasadded and the reaction mixture was stirred overnight at roomtemperature. The excess NaBH(OAc)₃ was decomposed with CH₃OH, and thesolvent was evaporated. The obtained residue was purified by Biotagecolumn chromatography (eluent: 100% CH₂Cl₂). The purest productfractions were collected and then the solvent was evaporated andco-evaporated with toluene to yield the title compound as a residue.

EXAMPLE 1003-Propyl-6-[3-(2,4,6-trimethyl-benzylamino)-phenoxy]-3,4-dihydro-quinazolin-2-ylamine

A mixture of{3-propyl-6-[3-(2,4,6-trimethyl-benzylamino)-phenoxy]-3,4-dihydro-quinazolin-2-yl}-carbamicacid tert-butyl ester (0.0001 mol) in 10% TFA in DCM (6 mL) was stirredin a reaction vial for 1 hour at room temperature and then the solventwas evaporated. The obtained residue was crystallized from CH₃CN, andthen the desired product was filtered off, washed with diisopropyl etherand dried under vaccum to yield the title compound as a solid.

mp 238° C.

EXAMPLE 101 4-Chloro-2-dimethoxymethyl-1-nitro-benzene

A mixture of 5-chloro-2-nitro-benzaldehyde (0.0792 mol),trimethoxy-methane (0.126 mol) and PTSA (0.00079 mol) in methanol (80mL) was refluxed until the 5-chloro-2-nitro-benzaldehyde had completelyreacted. The mixture was cooled, Na₂CO₃ was added, and the reactionmixture was stirred for 5 min. The mixture was filtered and the filtratewas evaporated under reduced pressure to yield the title compound as aresidue.

EXAMPLE 102 (3-Dimethoxymethyl-4-nitro-phenyl)-phenyl-methanone

Phenyl-acetonitrile (0.0793 mol) in DMA (100 ml) was stirred at roomtemperature and 50% NaH (0.0793 mol) was added portionwise. The mixturewas stirred at room temperature until the evolution of H₂ had ceased.TDA-1 (0.004 mol) was added and4-chloro-2-dimethoxymethyl-1-nitro-benzene (0.0793 mol) in DMA (30 mL)was added dropwise. The mixture was stirred at 60° C. and at 100° C.overnight. 50% NaH (0.0793 mol) was added again and the mixture wasstirred further at room temperature. The mixture was poured carefully onice/water and brought to about pH 6-7 with CH₃COOH. The product wasextracted with CH₂Cl₂. The organic layer was dried (MgSO₄) andevaporated. DMA was evaporated by use of high vacuum pump to yield thetitle compound as a residue.

A mixture of the title compound prepared as described above and K₂CO₃(0.0939 mol) in DMA (420 mL) was stirred at room temperature with airbubbling through the solution overnight. The mixture was poured in waterand extracted with CH₂Cl₂. The organic layer was dried (MgSO₄) andevaporated. The residue (26.4 g) was purified on a glass filter oversilica gel (eluent: hexane:CHCl₃ 20:80). The pure fractions werecollected and evaporated to yield the title compound as a residue.

EXAMPLE 103 5-Benzoyl-2-nitro-benzaldehyde

A mixture of (3-dimethoxymethyl-4-nitro-phenyl)-phenyl-methanone (0.0659mol) and 5N HCl (40 mL) in CH₃Cl (80 mL) was stirred at room temperatureovernight. Then the mixture was refluxed for 4 h. After cooling, theorganic layer was separated. The organic layer was alkalized by addingdropwise NH₄OH. The organic layer was washed with water, dried (MgSO₄)and evaporated. The residue (14.6 g) was crystallized from diisopropylether/EtOAc (50 mL:20 mL). The precipitate was filtered off, washed withdiisopropyl ether/EtOAc, diisopropyl ether and dried in vacuo at 50° C.to yield the title compound as a residue.

EXAMPLE 104(4-Amino-3-{[3-(cyclohexyl-methyl-amino)-propylamino]-methyl}-phenyl)-phenyl-methanone

A mixture of 5-benzoyl-2-nitrobenzaldehyde. (0.0058 mol) in THF (100 ml)was hydrogenated with 10% Pd/C (1 g) as a catalyst in the presence of 4%thiophene solution (1 mL). After uptake of H₂ (3 equiv), the mixture wasput in an autoclave. N-cyclohexyl, N-methyl-propane-1,3-diamine (0.01mol) and CaH₂ (0.5 g) were added and the mixture was reacted under 10atm of CO₂ and 50 atm of H₂ at 50° C. for 16 hours. When the reactionwas complete, the mixture was purified over silica gel on a glass filter(eluent: 90:10 CH₂Cl₂:(CH₃OH:NH₃)). The product fractions were collectedand the solvent was evaporated to yield the title compound as a residue.

EXAMPLE 105{2-Amino-3-[3-(cyclohexyl-methyl-amino)-propyl]-3,4-dihydro-quinazolin-6-yl}-phenyl-methanone(Compound #15)

A mixture of(3-{[3-(Cyclohexyl-methyl-amino)-propylamino]-methyl}-4-nitro-phenyl)-phenyl-methanone(0.0037 mol) in ethanol (40 mL) was stirred at room temperature.Cyanogen bromide (0.0055 mol) was added, and the reaction mixture wasstirred and refluxed for 4 hours, then cooled and the resultingprecipitate was filtered off and dried. This fraction was recrystallizedfrom CH₃CN, then filtered off and recrystallized from methanol, filteredoff, washed with diisopropyl ether, then dried to yield the titlecompound as a solid.

EXAMPLE 1063-(2-Amino-6-benzoyl-4H-quinazolin-3-yl)-N-cyclohexyl-N-methyl-propionamide

A mixture of3-(2-amino-5-benzoyl-benzylamino)-N-cyclohexyl-N-methyl-propionamide(0.017) prepared as described in Example 3 in ethanol (250 mL) wasstirred at room temperature and cyanogen bromide (0.027 mol) was added.The reaction mixture was stirred and refluxed for 3 hours, then cooled.The solvent was evaporated and the residue was crystallized from CH₃CN.The precipitate was filtered off and dried to yield the title compoundas a residue.

EXAMPLE 1073-(2-Amino-6-benzoyl-4H-quinazolin-3-yl)-N-cyclohexyl-N-methyl-propionamide

Cyanogen bromide (0.011 mol) was added to a solution of3-(2-amino-5-benzoyl-benzylamino)-N-cyclohexyl-N-methyl-propionamide(0.01 mol) in methanol (200 mL), stirred at room temperature. Thereaction solution was stirred over a weekend at room temperature, thenstirred and refluxed for an additional 5 h. The solvent was evaporatedto yield a residue. The residue was crystallized from ethyl acetate (100mLl). The resulting precipitate was filtered off and dried. The productfraction was recrystallized from 2-propanol (50 mL). The crystals werefiltered off and dried to yield the title compound as a residue.

EXAMPLE 1083-[2-Amino-6-(hydroxy-phenyl-methyl)-4H-quinazolin-3-yl]-N-cyclohexyl-N-methyl-propionamide

A mixture of3-(2-amino-6-benzoyl-4H-quinazolin-3-yl)-N-cyclohexyl-N-methyl-propionamide(0.0056 mol) in methanol (60 mL) and THF (30 mL) was stirred at roomtemperature. Then, NaBH₄ (0.0056 mol) was added and the reaction mixturewas stirred for 30 min at room temperature. The solvent was evaporated,and the residue was stirred in H₂O and then extracted with CH₂Cl₂. Theorganic layer was separated and dried, and the solvent was evaporated.The residue was purified by column chromatography over silica gel(eluent: 94:6 CH₂Cl₂:(CH₃OH:NH₃)). The purest product fractions werecollected and the solvent was evaporated to yield the title compound asa residue.

EXAMPLE 1093-(2-Amino-6-benzyl-4H-quinazolin-3-yl)-N-cyclohexyl-N-methyl-propionamide

A mixture of3-[2-amino-6-(hydroxy-phenyl-methyl)-4H-quinazolin-3-yl]-N-cyclohexyl-N-methyl-propionamide(0.0012 mol) in methanol (40 mL) and HCl/2-propanol (0.5 mL) washydrogenated at 50° C. with 10% Pd/C (0.4 g) as a catalyst. After uptakeof H₂ (1 equiv.), the reaction mixture was filtered over Dicalite andthe solvent was evaporated. The residue was triturated under diisopropylether, then the resulting solids were filtered off and dried to yieldthe title compound as a solid.

EXAMPLE 110 3-(3-Dimethoxymethyl-4-nitro-phenoxy)-phenylamine

K₂CO₃ (0.17 mol) and then 4-chloro-2-dimethoxymethyl-1-nitro-benzene(0.1 mol) was added to a solution of 3-amino-phenol (0.15 mol) in DMA(200 mL) and the reaction mixture was stirred at 130° C. for 24 hours.The mixture was poured out into water and extracted with diisopropylether. The extract was purified by column chromatography over silica gel(eluent: CH₂Cl₂:CH₃OH 100:0 to 65:35). The product fractions werecollected and the solvent was evaporated to yield the title compound asa residue.

EXAMPLE 111 3-(3-Dimethoxymethyl-4-nitro-phenoxy)-phenylamine

3-Amino-phenol (0.050 mol) was dissolved in DMA (100 ml). K₂CO₃ (0.050mol) was added. 4-Chloro-2-dimethoxymethyl-1-nitro-benzene (0.050 mol)was added and the reaction mixture was stirred overnight at 100° C.,then for 2 hours at 120° C. The reaction mixture was poured out intowater and this mixture was extracted with diisopropyl ether. Theseparated organic layer was dried, filtered and the solvent evaporated.The residue was purified by column chromatography over silica gel(eluent: CH₂Cl₂:CH₃OH 100:0 (to remove starting material) up to 70:30).The desired fractions were collected and the solvent was evaporated toyield the title compound as a residue.

EXAMPLE 112Cyclohexyl-[3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenyl]-amine

3-(3-Dimethoxymethyl-4-nitro-phenoxy)-phenylamine (0.0125 mol) wasdissolved in DCE (150 mL), and cyclohexanone (0.0125 mol) was added,followed by NaBH(OAc)₃ (0.0187 mol). The reaction mixture was stirredovernight at room temperature. Some extra NaBH(OAc)₃ was added, and thereaction mixture was stirred overnight at room temperature. A 10% NaOHsolution (150 mL) was added, and this mixture was extracted withdiisopropyl ether. The separated organic layer was dried (MgSO₄) andfiltered, and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: 20:80 up to 5:95hexane:CH₂Cl₂). The product fractions were collected and the solvent wasevaporated to yield the title compound as a residue.

EXAMPLE 113Cyclohexyl-[3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenyl]-carbamic acidbenzyl ester

A mixture ofcyclohexyl-[3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenyl]-amine (0.00868mol) and Na₂CO₃ (0.02083 mol) in H₂O (15 mL) and THF (75 mL) was stirredat 5° C. A solution of benzyl chloroformate (0.0104 mol) in THF (25 mL)was added dropwise over 15 min at 5° C. The resultant reaction mixturewas stirred for 21 hours at room temperature. This mixture was extractedwith diisopropyl ether. The separated organic layer was dried (MgSO₄)and filtered, and the solvent was evaporated. The residue (0.00633 molA) was reacted again with benzyl chloroformate (1.3 g, 0.0076 mol) andTEA (1.53 g, 0.0152 mol) in DCM (70 mL) under the same conditions asabove. The residue was purified by column chromatography over silica gel(eluent: 95:5 CH₂Cl₂:hexane). The product fractions were collected andthe solvent was evaporated to yield the title compound as a residue.

EXAMPLE 114 Cyclohexyl-[3-(3-formyl-4-nitro-phenoxy)-phenyl]-carbamicacid benzyl ester

Cyclohexyl-[3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenyl]-carbamic acidbenzyl ester (0.0027 mol) was dissolved in THF (12 mL). Water (6 mL) and12N HCl (3 mL) were added and the reaction mixture was stirred for 42hours at room temperature. Water was added. This mixture was extractedwith diisopropyl ether. The organic layer was separated, washed with a10% aqueous NaHCO₃ solution and then with water, dried (MgSO₄) andfiltered. The solvent was then evaporated to yield a residue that wasused in the next reaction step without further purification.

EXAMPLE 115Cyclohexyl-[3-(4-nitro-3-propylaminomethyl-phenoxy)-phenyl]-carbamicacid benzyl ester

A mixture of propylamine (0.00356 mol) in DCE (70 mL) was stirred atroom temperature.Cyclohexyl-[3-(3-formyl-4-nitro-phenoxy)-phenyl]-carbamic acid benzylester (0.00274 mol) was added. NaBH(OAc)₃ (0.00438 mol) was added. Thereaction mixture was stirred overnight at room temperature. A 10% NaOHsolution was added and this mixture was extracted with diisopropylether. The separated organic layer was dried (MgSO₄), filtered and thesolvent evaporated. The residue was purified by column chromatographyover silica gel (eluent: 100:0 to 96:4 CH₂Cl₂:CH₃OH ). The productfractions were collected and the solvent was evaporated to yield thetitle compound as a residue.

EXAMPLE 116[3-(4-Amino-3-propylaminomethyl-phenoxy)-phenyl]-cyclohexyl-carbamicacid benzyl ester

A mixture ofcyclohexyl-[3-(4-nitro-3-propylaminomethyl-phenoxy)-phenyl]-carbamicacid benzyl ester (0.00181 mol) in methanol (50 mL) was hydrogenatedwith 5% Pt/C (0.5 g) as a catalyst in the presence of thiophene solution(1 mL). After uptake of H₂ (3 equiv), the catalyst was filtered off andthe filtrate was evaporated to yield the title compound as a residuewhich was used in subsequent reactions without further purification.

EXAMPLE 117[3-(2-Amino-3-propyl-3,4-dihydro-quinazolin-6-yloxy)-phenyl]-cyclohexyl-carbamicacid benzyl ester

A mixture of[3-(4-amino-3-propylaminomethyl-phenoxy)-phenyl]-cyclohexyl-carbamicacid benzyl ester (0.0018 mol) and cyanogen bromide (0.00234 mol) inethanol (60 mL) was stirred and refluxed for 3 hours and then wascooled. The ethanol solvent was evaporated. The residue was trituratedunder diisopropyl ether and ethanol, filtered off, and dried to yieldthe title compound as a solid.

EXAMPLE 118Cyclohexylmethyl-[3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenyl]-amine

The reaction was completed under N₂. Cyclohexanecarboxaldehyde (0.01mol) and then NaBH(OAc)₃ (0.015 mol) were added to a solution of3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenylamine (0.01 mol) in DCE (130mL). The reaction mixture was stirred overnight at room temperature andwashed with a saturated NaHCO₃ solution. The organic layer wasseparated, dried (MgSO₄) and filtered, and the solvent was evaporated toyield the title compound as a residue.

EXAMPLE 119 5-[3-(Cyclohexylmethyl-amino)-phenoxy]-2-nitro-benzaldehyde

12N HCl (2 mL) and H₂O (4 mL) were added to a mixture ofcyclohexylmethyl-[3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenyl]-amine(0.0055 mol) in THF (17 mL), and the reaction mixture was stirredovernight at room temperature. H₂O was added, and the mixture wasextracted with diisopropyl ether. The organic layer was washed with a10% NaHCO₃ solution, dried (MgSO₄), filtered off and the solvent wasevaporated. The residue was purified by short column chromatography(eluent: 100% CH₂Cl₂). The purest product fractions were collected andthe solvent was evaporated to yield the title compound as a residue.

EXAMPLE 120Cyclohexylmethyl-[3-(4-nitro-3-propylaminomethyl-phenoxy)-phenyl]-amine

NaBH(OAc)₃ (0.0080 mol) was added to a mixture of propylamine (0.0054mol) and 5-[3-(cyclohexylmethyl-amino)-phenoxy]-2-nitro-benzaldehyde(0.00054 mol) in DCE (100 mL). Then the reaction mixture was stirredovernight at room temperature and washed with a saturated NaHCO₃solution. The organic layer was separated, dried (MgSO₄), and filtered,and the solvent was evaporated. The residue was purified by columnchromatography (eluent: 100% CH₂Cl₂). The purest product fractions werecollected and the solvent was evaporated to yield the title compound asa residue.

EXAMPLE 1212-Amino-5-[3-[(cyclohexylmethyl)amino]phenoxy]-N-propyl-benzenemethamine

A mixture ofcyclohexylmethyl-[3-(4-nitro-3-propylaminomethyl-phenoxy)-phenyl]-amine(0.0037 mol) in methanol (50 mL) was hydrogenated with 10% Pd/C (0.5 g)as a catalyst in the presence of thiophene solution (0.5 mL). Afteruptake of H₂ (3 equiv.), the reaction mixture was filtered over Dicaliteand the filtrate was evaporated. The residue was purified by columnchromatography (eluent: 98:2 CH₂Cl₂:CH₃OH). The purest product fractionswere collected and the solvent was evaporated to yield the titlecompound as a residue.

EXAMPLE 1226-[3-(Cyclohexylmethyl-amino)-phenoxy]-3-propyl-3,4-dihydro-quinazolin-2-ylamineand[3-(2-Amino-3-propyl-3,4-dihydro-quinazolin-6-yloxy)-phenyl]-cyclohexylmethyl-cyanamide

Cyanogen bromide (0.0030 mol) was added to a mixture of2-amino-5-[3-[(cyclohexylmethyl)amino]phenoxy]-N-propyl-benzenemethamine(0.0027 mol) in ethanol (100 mL) and the reaction mixture was stirredfor 2 hours, and the solvent was evaporated. The residue was convertedinto the free base with aqueous NaHCO₃ solution, and the mixture wasextracted with CH₂Cl₂. The organic layer was separated, dried (MgSO₄),and filtered, and the solvent was evaporated. The residue was separatedby reversed-phase high-performance liquid chromatography over RP-18,then two product fractions were collected and the solvent was evaporatedto yield the title compounds, each as a white solid.

EXAMPLE 1233-(2-Amino-5-benzoyl-benzylamino)-N-cyclohexyl-N-methyl-propionamide

3-(5-Benzoyl-2-nitro-benzylamino)-N-cyclohexyl-N-methyl-propionamide(0.01 mol) was converted into its corresponding free base. A mixture ofthe free base (0.01 mol) in methanol (200 mL) was hydrogenated underatmospheric conditions, with 5% Pt/C (2 g) as a catalyst in the presenceof 4% thiophene solution (1 mL). After uptake of H₂ (3 equiv.), thecatalyst was filtered off and the filtrate was evaporated. Toluene wasadded to the residue, then evaporated again to yield the title compoundas a residue.

EXAMPLE 124 (3-Dimethoxymethyl-4-nitro-phenyl)-phenyl-methanone

(3-Dimethoxymethyl-4-nitro-phenyl)-morpholin-4-yl-phenyl-acetonitrile(0.7 mol) in CH₃CO₂H (1500ml) was stirred and refluxed for 30 min. Themixture was poured on ice/water and extracted with diisopropyl ether.The organic layer was washed with alkalic water and water. The organiclayer was dried (MgSO₄) and evaporated to yield a residue. The aqueouslayers which contained product were extracted with CH₂Cl₂. The organiclayer was dried (MgSO₄) and evaporated to yield a residue. The combinedresidues were purified on a glass filter over silica gel (eluent:CH₂Cl₂). The pure fractions were collected and evaporated to yield thetitle compound as a residue.

EXAMPLE 125 3-(3-Dimethoxymethyl-4-nitro-phenoxy)-phenylamine

K₂CO₃ (0.34 mol), followed by 4-chloro-2-dimethoxymethyl-1-nitro-benzene(0.2 mol) was added to a solution of 3-amino-phenol (0.3 mol) in DMA(400 mLl) and the reaction mixture was stirred overnight at 130° C. Themixture was cooled to room temperature and the solvent was evaporated.The residue was taken up in H₂O and the mixture was extracted withCH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered off andthe solvent was evaporated. The residue was purified by columnchromatography (eluent: CH₂Cl₂ 100%). The product fractions werecollected and the solvent was evaporated to yield the title compound asa residue.

EXAMPLE 126 3-(3-Dimethoxymethyl-4-nitro-phenoxy)-phenylamine

K₂CO₃ (0.076 mol) was added to a mixture of 3-amino-phenol (0.069 mol)in ethanol (200 mL) and the mixture was stirred for 10 min at roomtemperature, then 4-chloro-2-dimethoxymethyl-1-nitro-benzene (0.046 mol)was added and the reaction mixture was stirred for 16 hours at refluxtemperature. The mixture was allowed to reach room temperature and thesolvent was evaporated. The residue was washed with water and extracted2 times with CH₂Cl₂. The organic layer was separated, dried (MgSO₄),filtered off and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂ 100%). The purestproduct fractions were collected and the solvent was evaporated to yieldthe title compound as a residue.

EXAMPLE 127N-[3-(3-Dimethoxymethyl-4-nitro-phenoxy)-phenyl]-benzenesulfonamide

A mixture of 3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenylamine (0.013mol) in THF (100 mL) and TEA (200 mL) was stirred at room temperatureand a mixture of benzenesulfonyl chloride (0.013 mol) in THF (50 mL) wasadded dropwise, then the reaction mixture was stirred overnight at roomtemperature and again overnight at 60° C. The solvent was evaporated andthe residue was stirred in H₂O. After extraction with CH₂Cl₂, theorganic layer was separated, dried, filtered off and the solvent wasevaporated. The residue was purified by Biotage column chromatography(eluent: CH₂Cl₂ 100%). The purest product fractions were collected andthe solvent was evaporated to yield the title compound as a residue.

EXAMPLE 128 Ethenesulfonic acid cyclohexyl-methyl-amide

A mixture of N-methylcyclohexylamine (0.048 mol) and TEA (0.053 mol) inDCM (200 mL) was cooled in an ice bath to 5° C., and then a solution of2-chloro-ethanesulfonyl chloride (0.048 mol, 97%) in DCM (20 mL) wasadded dropwise. The reaction mixture was stirred for 2 hours at roomtemperature and then was washed with H₂O. The organic layer wasseparated, dried (MgSO₄), and filtered, and the solvent was evaporatedto yield the title compound as a residue.

EXAMPLE 129 2-Amino-ethanesulfonic acid cyclohexyl-methyl-amide

Ethenesulfonic acid cyclohexyl-methyl-amide (0.0167 mol) was reactedwith a mixture of methanol/ammonia (10 mL) in an autoclave for 16 hoursat room temperature, and then the solvent was evaporated. The residuewas purified by column chromatography (eluent: 90:10CH₂Cl₂:(CH₃OH:NH₃)). The purest product fractions were collected and thesolvent was evaporated to yield the title compound as a residue.

EXAMPLE 130 2-(5-Benzoyl-2-nitro-benzylamino)-ethanesulfonic acidcyclohexyl-methyl-amide

NaBH(OAc)₃ (0.014 mol) was added to a mixture of 2-amino-ethanesulfonicacid cyclohexyl-methyl-amide (0.0091 mol) and5-benzoyl-2-nitro-benzaldehyde (0.0091 mol) in DCE (150 mL). Thereaction mixture was then stirred overnight at room temperature and thenwashed with saturated NaHCO₃ solution. The organic layer was separated,dried (MgSO₄), and filtered, and the solvent was evaporated. The residuewas purified by column chromatography (eluent: 100% CH₂Cl₂). The purestproduct fractions were collected and the solvent was evaporated to yieldthe title compound as a residue.

EXAMPLE 131 2-(2-Amino-5-benzoyl-benzylamino)-ethanesulfonic acidcyclohexyl-methyl-amide

A mixture of 2-(5-benzoyl-2-nitro-benzylamino)-ethanesulfonic acidcyclohexyl-methyl-amide (0.009 mol) in methanol (150 mL) washydrogenated with 10% Pd/C (1 g) as a catalyst in the presence ofthiophene solution (1 mL). After uptake of H₂ (3 equiv.), the catalystwas filtered off, and the filtrate was evaporated. The residue waspurified by column chromatography over Biotage (eluent: 98:2CH₂Cl₂:CH₃OH). The purest product fractions were collected and thesolvent was evaporated to yield the title compound as a residue.

EXAMPLE 132 2-(2-Amino-6-benzoyl-4H-quinazolin-3-yl)-ethanesulfonic acidcyclohexyl-methyl-amide

A mixture of 2-(2-amino-5-benzoyl-benzylamino)-ethanesulfonic acidcyclohexyl-methyl-amide (0.0054 mol) and cyanogen bromide (0.0080 mol)in ethanol (100 mL) was stirred and refluxed for 2 hours, and then thereaction mixture was cooled to room temperature. After filtration, thefilter residue was washed with diisopropyl ether and dried under vacuumto yield the title compound as a solid.

EXAMPLE 133 3-(3-Dimethoxymethyl-4-nitro-phenoxy)-benzonitrile

A mixture of 3-cyanophenol (0.38 mol) in ethanol (600 mL) was stirred atroom temperature and K₂CO₃ (0.29 mol) was added.5-fluoro-2-nitrobenzaldehyde (0.18 mol) was added, and the reactionmixture was stirred and refluxed for 4 hours. The solvent wasevaporated, and the residue was stirred in water and extracted withCH₂Cl₂. The organic layer was separated, dried, filtered off and thesolvent was evaporated. The residue was triturated under diisopropylether, and then the formed solids were filtered off and dried to yieldthe title compound.

EXAMPLE 134 3-(3-Formyl-4-nitro-phenoxy)-benzonitrile

A mixture of 3-(3-dimethoxymethyl-4-nitro-phenoxy)-benzonitrile (0.068mol) in THF (140 ml) was stirred at room temperature, then 12N HCl (55ml) and water (55 ml) were added and the reaction mixture was stirredovernight at room temperature. The mixture was stirred in H₂O andextracted with DIPE. The organic layer was separated, washed with a 10%NaHCO₃ solution, separated again, dried, filtered off and the solventwas evaporated. The obtained residue was stirred in DIPE, then thedesired product was filtered off and dried to yield the title compoundas a residue.

EXAMPLE 135 3-(4-Nitro-3-propylaminomethyl-phenoxy)-benzonitrile

The following reaction was completed under N₂. A mixture of3-(3-formyl-4-nitro-phenoxy)-benzonitrile (0.056 mol) and propylamine(0.059 mol) in DCE (450 ml) was stirred at room temperature, thenNaBH(OAc)₃ (0.063 mol) was added. The reaction mixture was stirredovernight at room temperature. A saturated NaHCO₃ solution was added andthe layers were separated. The organic layer was dried, filtered off andthe solvent was evaporated. The residue was purified over silica gelfilter (eluent: CH₂Cl₂/CH₃OH 99/1). The purest product fractions werecollected and the solvent was evaporated to yield the title compound asa residue.

EXAMPLE 136 3-(4-Amino-3-propylaminomethyl-phenoxy)-benzonitrile

A mixture of 3-(4-nitro-3-propylaminomethyl-phenoxy)-benzonitrile (0.045mol) in methanol (250 ml) was hydrogenated with 10% Pd/C (2 g) as acatalyst in the presence of thiophene solution (2 ml). After uptake ofH₂ (3 equiv.), the reaction mixture was filtered over dicalite and thefiltrate was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 98/2). The purestproduct fractions were collected and the solvent was evaporated to yieldthe title compound as a residue.

EXAMPLE 1373-(2-Amino-3-propyl-3,4-dihydro-quinazolin-6-yloxy)-benzonitrile

A mixture of 3-(4-Amino-3-propylaminomethyl-phenoxy)-benzonitrile (0.032mol) in ethanol (400 ml) was stirred at room temperature and cyanogensbromide (0.038 mol) was added. The reaction mixture was stirred andrefluxed for 2 hours. After cooling, the precipitate was filtered off,washed with DIPE and dried to yield the title compound.

The filtrate was evaporated and the obtained residue was crystallisedfrom CH₃CN/DIPE, then the precipitate was filtered off, washed with DIPEand dried to yield residue.

EXAMPLE 138 3-(2-Amino-3-propyl-3,4-dihydro-quinazolin-6-yloxy)-benzoicacid

A mixture of3-(2-amino-3-propyl-3,4-dihydro-quinazolin-6-yloxy)-benzonitrile (0.0013mol), prepared as described in Example 75, in concentrated H₂SO₄ (5 mL)and water (5 mL) was stirred and refluxed for 2 hours. The reactionmixture was then cooled, and the resulting solids were filtered off. Theobtained filter residue was washed with ice-water and dried to yield thetitle compound as a solid.

EXAMPLE 139 3-(2-Amino-3-propyl-3,4-dihydro-quinazolin-6-yloxy)-benzoylchloride

A mixture of 3-(2-amino-3-propyl-3,4-dihydro-quinazolin-6-yloxy)-benzoicacid (0.0009 mol) in SOCl₂ (2 mL) and DCM (10 mL) was stirred for 2hours at room temperature and then the solvent was evaporated. Theobtained residue was stirred in toluene and the solvent was evaporatedagain to yield the title compound as a residue.

EXAMPLE 1403-(2-Amino-3-propyl-3,4-dihydro-quinazolin-6-yloxy)-N-(2,4,6-trimethyl-benzyl)-benzamide

A mixture of 3-(2-amino-3-propyl-3,4-dihydro-quinazolin-6-yloxy)-benzoylchloride (0.0008 mol) in DCM (20 mL) was stirred at 0° C. and2,4,6-trimethylbenzylamine (0.0013 mol) was added. Then TEA (q.s.) wasadded, and the reaction mixture was stirred at room temperature. Themixture was stirred in H₂O and the organic layer was separated. Theremaining layer was washed again with H₂O, then the organic layer wasseparated, dried, and-filtered, and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (gradienteluent: CH₂Cl₂:(CH₃OH:NH₃)). The purest product fractions werecollected, and the solvent was evaporated. The residue was trituratedunder diisopropyl ether:CH₃CN, and then the resulting solids werefiltered off and dried to yield the title compound as a solid.

EXAMPLE 141 4-Chloro-2-dimethoxymethyl-1-nitro-benzene

A mixture of 5-chloro-2-nitro-benzaldehyde (0.0792 mol),trimethoxy-methane (0.126 mol) and PTSA (0.00079 mol) in methanol (80m)was refluxed until the 5-chloro-2-nitro-benzaldehyde had completelyreacted. The mixture was cooled, Na₂CO₃ was added and stirred for 5min.The mixture was filtered off and the filtrate was evaporated underreduced pressure to yield the title compound as a residue.

EXAMPLE 142 3-(3-Dimethoxymethyl-4-nitro-phenylsulfanyl)-phenylamine

K₂CO₃ (0.085 mol) was added to a mixture of 3-aminobenzenethiol (0.075mol) in DMA (150 mL). Then 4-chloro-2-dimethoxymethyl-1-nitrobenzene(0.050 mol) was added and the reaction mixture was stirred for 2 hoursat 80° C. H₂O was added and the mixture was extracted with diisopropylether. The crude product was purified by column chromatography (eluent:70:30 CH₂Cl₂/hexane up to 99:1 CH₂Cl₂:CH₃OH). The product fractions werecollected, and the solvent was evaporated to yield the title compound asa residue.

EXAMPLE 143N-[3-(3-Dimethoxymethyl-4-nitro-phenylsulfanyl)-phenyl]-benzenesulfonamide

A mixture of 3-(3-dimethoxymethyl-4-nitro-phenylsulfanyl)-phenylamine(0.0384 mol) and TEA (0.0578 mol) in THF (q.s.) was cooled to 5° C., andphenylsulfonyl chloride (0.0384 mol) was added dropwise at 5° C. Then,the reaction mixture was reacted at room temperature, and purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂). The productfractions were collected and the solvent was evaporated to yield thetitle compound as a residue.

EXAMPLE 144N-[3-(3-Formyl-4-nitro-phenylsulfanyl)-phenyl]-benzenesulfonamide

A mixture ofN-[3-(3-dimethoxymethyl-4-nitro-phenylsulfanyl)-phenyl]-benzenesulfonamide(0.027 mol) in 12N HCl (25 mL), THF (75 mL), and water (50 mL) wasstirred overnight at room temperature, and then the mixture wasextracted with EtOAc. The extract was washed with H₂O and then with asaturated Na₂CO₃ solution. The solvent was evaporated, and the residuewas purified by column chromatography over silica gel (eluent: CH₂Cl₂).The product fractions were collected and the solvent was evaporated toyield the title compound as a residue.

EXAMPLE 145N-[3-(3-Formyl-4-nitro-benzenesulfinyl)-phenyl]-benzenesulfonamide

A mixture ofN-[3-(3-formyl-4-nitro-phenylsulfanyl)-phenyl]-benzenesulfonamide(0.0034 mol) and 3-Chloro-benzenecarboperoxoic acid (also known as MCPBAor meta-chloroperbenzoic acid) (0.7 g; 75%) in CHCl₃ (q.s.) was stirredfor 4 hours at room temperature. Then a NaHCO₃ solution was added, andthe reaction mixture was stirred. The organic layer was separated,dried, and filtered, and the solvent was evaporated. The residue waspurified by column chromatography over Biotage (gradient eluent:CH₂Cl₂:CH₃OH). The purest product fractions were collected, and thesolvent was evaporated to yield the title compound as a residue.

EXAMPLE 146N-[3-(4-Nitro-3-propylaminomethyl-benzenesulfinyl)-phenyl]-benzenesulfonamide

The following reaction was run under N₂. A mixture ofN-[3-(3-formyl-4-nitro-benzenesulfinyl)-phenyl]-benzenesulfonamide(0.0023 mol) and propylamine (0.0025 mol) in DCE (50 mL) was stirred atroom temperature and NaBH(OAc)₃ (0.8 g) was added. The reaction mixturewas stirred overnight at room temperature, and then a NaHCO₃ solutionwas added. The organic layer was separated, dried, and filtered, and thesolvent was evaporated to yield the title compound as a residue.

EXAMPLE 147N-[3-(4-Amino-3-propylaminomethyl-benzenesulfinyl)-phenyl]-benzenesulfonamide

A mixture ofN-[3-(4-nitro-3-propylaminomethyl-benzenesulfinyl)-phenyl]-benzenesulfonamide(0.0019 mol) in methanol (100 mL) was hydrogenated with 10% Pd/C (0.5 g)as a catalyst. After uptake of H₂ (3 equiv.), the reaction mixture wasfiltered over Dicalite, and the filtrate was evaporated. The residue wasfiltered over silica gel (eluent: 95:5 CH₂Cl₂:CH₃OH),and then the purestproduct fractions were collected, and the solvent was evaporated toyield the title compound as a residue.

EXAMPLE 148N-[3-(2-Amino-3-propyl-3,4-dihydro-quinazoline-6-sulfinyl)-phenyl]-benzenesulfonamide

A mixture ofN-[3-(4-amino-3-propylaminomethyl-benzenesulfinyl)-phenyl]-benzenesulfonamide(0.00090 mol) and cyanogen bromide (0.00094 mol) in ethanol (30 mL) wasstirred overnight at room temperature, and then the solvent wasevaporated. The residue was triturated under diisopropyl ether, and thesolids were filtered off. The residue was converted into the free basewith a NaOH solution. The mixture was extracted with CH₂Cl₂, but theproduct stayed in the aqueous layer so the mixture was desalted withNaCl to yield an oil. The solvent was decanted, and the remaining oilwas triturated under CH₃CN. The resulting solids were filtered off,washed with diisopropyl ether, and dried to yield the title compound asa solid.

EXAMPLE 1492-[4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4S-(tetrahydro-pyran-4-yl)-butyrylamino]-3R-tert-butoxy-propionicacid and2-[4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4S-(tetrahydro-pyran-4-yl)-butyrylamino]-3R-hydroxy-propionicacid

Step A:

To an ice cooled solution of H-D-Ser(t-Butyl)OCH₃.HCl,4-tert-butoxycarbonylamino-4-(4-tetrahydropyranyl)-butyric acid (0.5 g,1.8 mmol) and HOBT (0.32 g, 2.4 mmol) in CH₂Cl₂ (50 mL), TEA (0.7 mL)was added followed by addition of 1,3-dimethylaminopropyl-3-ethylcarbodiimide (EDC, 0.45 g, 2.4 mmol). The reaction mixturewas allowed to warm to room temperature and stirred overnight. Ethylacetate (200 mL) was added. The solution was washed with dilute- HClacid solution (about 0.1 N, 50 mL), saturated aqueous NaHCO₃, andaqueous NaCl solution. The organic layer was dried with MgSO₄. Afterfiltration, the EtOAc was evaporated to yield3-(R)-tert-butoxy-2-[4-tert-butoxycarbonylamino-4S-(tetrahydro-pyran-4-yl)-butyrylamino]-propionicacid methyl ester as a a crude oil.

MH⁺444.9

Step B:

A solution of the oil isolated in Step A (0.8 g, 1.8 mmol) in TFA (5% inCH₂Cl₂, 50 mL) was stirred at room temperature 4 hours. The solvent andmost of the TFA was evaporated, and EtOAc (100 mL) was added. Theorganic extract was washed with aqueous NaHCO₃ solution and brine. Theorganic layer was dried with MgSO₄, filtered, and evaporated to yield2-[4-amino-4-(S)-(tetrahydro-pyran-4-yl)-butyrylamino]-3-(R)-tert-butoxy-propionicacid methyl ester as an oil.

MH⁺345.0

Step C:

A solution of the oil isolated in Step C (0.5 g, 1.4 mmol) and2-nitro-5-phenoxy-benzaldehyde (0.35 g, 1.4 mmol) in methylene chloride(50 mL) was stirred at room temperature for 5 hours, and then NaBH(OAc)₃(0.6g, 2.8 mmol) was added. The reaction mixture was stirred at roomtemperature 3 hours. The reaction mixture was then poured into EtOAc(100 mL). The organic layer was washed with brine, dried with MgSO₄,filtered, and evaporated. Purification by column chromatography (1:1heptane/EtOAc) yielded3-(R)-tert-butoxy-2-[4-(2-nitro-5-phenoxy-benzylamino)-4-(S)-(tetrahydro-pyran-4-yl)-butyrylamino]-propionicacid methyl ester as an oil.

MH⁺571.9

Step D:

To a solution of the oil isolated in Step C (0.37 g, 0.65 mmol) in MeOH(10 mL) was added 0.05 g of 10% Pd on activated carbon under N₂. Thereaction mixture was subjected to hydrogenation under 5 psi for 2 hour.The catalyst was removed by filtration, and the filtrate was evaporatedto yield2-[4-(2-amino-5-phenoxy-benzylamino)-4-(S)-(tetrahydro-pyran-4-yl)-butyrylamino]-3-(R)-tert-butoxy-propionicacid methyl ester as an oil.

MH⁺542.0

Step E:

To a solution of the oil isolated in Step D (0.29 g, 0.53 mmol) wasadded BrCN (3M in CH₂Cl₂, 0.18 mL) in EtOH (20 mL) was stirred at roomtemperature overnight. The EtOH was evaporated to yield an oil which wasstirred in diethyl ether (50 mL) for 30 min. The precipitate whichformed was collected to yield2-[4-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-4-(S)-(tetrahydro-pyran-4-yl)-butyrylamino]-3-(R)-tert-butoxy-propionicacid methyl ester as a solid, as its corresponding HBr salt.

MH⁺567.9

Step F:

To a solution of the solid isolated in Step E (0.4 g, 0.7 mmol) in MeOH(20 mL) and water (1 mL) was added LiOH (0.04 g, 1.7 mmol). The solutionwas stirred at room temperature overnight and then was acidified (pH=2)with citric acid. The MeOH was removed by vacuum to yield a crude oilwhich was purified by Gilson HPLC to yield2-[4-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-4-(S)-(tetrahydro-pyran-4-yl)-butyrylamino]-3-(R)-tert-butoxy-propionicacid as a TFA salt.

MH⁺553.8

¹H NMR (300 MHz, CDCl₃): δ1.17 (s, 9H), 1.60-2.40 (m, 9H), 3.28-3.36 (m,2H), 3.62 (m, 1H), 3.83-3.97 (m, 4H), 4.14 (d, J=14.4 Hz, 1H), 4.32 (d,J=14.4 Hz, 1H), 4.48 (m, 1H), 6.73 (d, J=2.3 Hz, 1H,), 6.95 (m, 3H), 7.1(m, 2H), 7.30 (t, J=7.6 Hz, 2H)

Step G:

A solution of the salt isolated in Step H (0.4 g) in 30% TFA/CH₂Cl₂ (5mL) was stirred at room temperature overnight. The solvent wasevaporated to yield a crude oil which was purified by Gilson HPLC toyield2-[4-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-4S-(tetrahydro-pyran-4-yl)-butyrylamino]-3R-hydroxy-propionicacid as a TFA salt.

MH⁺497.9

¹H NMR (300 MHz, CDCl₃): δ1.27-1.36 (m, 4H), 1.67-1.78 (m, 4H),2.17-2.46 (m, 3H), 3.23-3.34 (m, 2H), 3.85-3.95 (m, 5H), 3.83-3.97 (m,4H), 4.15 (d, J=14.3 Hz, 1H), 4.33-(d, J=14.3 Hz, 1H), 4.48 (m,1H), 6.73(d, J=2.0 Hz, 1H), 6.95 (m, 4H), 7.11 (t, J=7.38 Hz, 1H), 7.3 (m, 2H).

EXAMPLE 1502-{[4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4S-(tetrahydro-pyran-4-yl)-butyryl]-methyl-amino}-3R-benzyloxy-propionicacid

Step A:

A solution of Boc-D-Ser(Benzyl)-OH (1 g, 3.4 mmol), CH₃I (2M in diethylether, 16 mL) in DMF (16 mL) was cooled to 0° C. before NaH (60% wt.,0.31 g, 7.2 mmol) was added. The reaction mixture was stirred under 0°C. for 5 h before overnight storage in freezer. Additional CH₃1 (2M indiethyl ether, 5 mL) was added and stirring was continued for 5 h. Thereaction was quenched with water and acidified to pH 3 with HCl beforeextraction with diethyl ether (4×100 mL). The organic layer was driedwith MgSO₄ and evaporated to yield3R-benzyloxy-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid as acrude oil.

MH⁺210.0 (MH⁺−Boc)

Step B:

A solution of the oil isolated in Step A (1.1 g, 3.4 mmol), concentratedH₂SO₄ (0.7 mL) in MeOH (50 mL) was refluxed for 24 h. Additional H₂SO₄(1 mL) was added, and the reaction mixture was refluxed for anadditional 5 h. The MeOH was removed under vacuum. To the reactionmixture was then added CH₂Cl₂ (100 mL), and the aqueous layer wasbasified with NH₄OH. The layers were separated, and the aqueous layerwas extracted with CH₂Cl₂ (2×100 mL). The organic layers were combined,dried with MgSO₄, filtered, and evaporated to yield3R-benzyloxy-2-methylamino-propionic acid methyl ester as an oil.

MH⁺223.9

Step C:

To an ice cooled solution of the oil isolated in Step C (0.7 g, 3 mmol),4-tert-butoxycarbonylamino-4-cyclohexyl-butyric acid (0.76 g, 3 mmol)and HOBT (0.6 g, 4.4 mmol) in CH₂Cl₂ (100 mL), TEA (0.87 mL, 7 mmol) wasadded followed by addition of 1,3-dimethylaminopropyl-3-ethylcarbodiimide (EDC, 0.8 g, 4.2 mmol). The reaction mixturewas allowed to warm to room temperature and stirred overnight. Thereaction mixture was acidified by adding aqueous citric acid solution.This mixture was then extracted by EtOAc (2×100 mL). The organic layerswere combined, dried with MgSO₄ and evaporated to yield3R-benzyloxy-²-{[4-tert-butoxycarbonylamino-4S-(tetrahydro-pyran-4-yl)-butyryl]-methyl-amino}-propionicacid methyl ester as an oil.

MH⁺492.9

Step D:

A solution of the oil isolated in Step C (1.5 g, 3 mmol) in TFA (10% inCH₂Cl₂, 100 mL) was stirred at room temperature for 5 hours. The solventand most of TFA was evaporated to yield a solution which was basifiedwith aqueous saturated NaHCO₃ solution and extracted with CH₂Cl₂ (2×100mL). The organic layers were combined, dried with MgSO₄ and evaporatedto yield2-{[4-amino-4S-(tetrahydro-pyran-4-yl)-butyryl]-methyl-amino}-3R-benzyloxy-propionicacid methyl ester as an oil.

MH⁺392.9

Step E:

A solution of the oil isolated in Step D (0.5 g, 1.3 mmol),2-nitro-5-phenoxy-benzaldehyde (0.33 g, 1.3 mmol) in methylene chloride(50 mL) was stirred at room temperature overnight. NaBH(OAc)₃ (0.58 g,2.6 mmol) was added, and the reaction mixture was stirred at roomtemperature for 5 hours. The reaction mixture was then poured into EtOAc(100 mL). The organic layer was washed with brine, dried with MgSO₄,filtered, and evaporated. Column chromatography (1:1 heptane:EtOAc)yielded3R-benzyloxy-2-{methyl-[4-(2-nitro-5-phenoxy-benzylamino)-4S-(tetrahydro-pyran-4-yl)-butyryl]-amino}-propionicacid methyl ester as an oil.

MH⁺620.8

Step F:

To a solution of the oil isolated in Step E (0.5 g, 0.8 mmol) in MeOH(10 mL) was added 0.1 g of 10% Pd on activated carbon under N₂. Thereaction mixture was subjected to hydrogenation under 5 psi for 2 h. Thecatalyst was removed by filtration, and the filtrate was evaporated toyield2-{[4-(2-amino-5-phenoxy-benzylamino)-4S-(tetrahydro-pyran-4-yl)-butyryl]-methyl-amino}-3R-benzyloxy-propionicacid methyl ester as an oil.

MH⁺590.8

Step G:

A solution of the oil isolated in Step F (0.48 g, 0.8 mmol), BrCN (3M inCH₂Cl₂, 0.41 mL) in EtOH (50 mL) was stirred at room temperatureovernight. The EtOH was evaporated. The resulting oil was stirred indiethyl ether (50 mL) for 30 min, and the precipitate that formed wascollected to yield2-{[4-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-4S-(tetrahydro-pyran-4-yl)-butyryl]-methyl-amino}-3R-benzyloxy-propionicacid methyl ester as a solid, as its corresponding HBr salt.

MH⁺615.8

Step H:

To a solution of the solid isolated in Step G (0.24 g, 0.4 mmol) in MeOH(30 mL) was added 1 N NaOH (0.6 mL). The reaction mixture was stirred atroom temperature overnight before acidification with citric acid. Themethanol was evaporated to yield a crude oil which was purified byGilson HPLC to yield2-{[4-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-4S-(tetrahydro-pyran-4-yl)-butyryl]-methyl-amino}-3R-benzyloxy-propionicacid as its TFA salt.

MH⁺601.7

¹H NMR (300 MHz, CDCl₃): δ1.18-2.18 (m, 11H), 2.9 (s, 3H), 3.27-3.36 (m,2H), 3.8-4.0 (m, 4H), 4.18-4.25 (m, 2H), 4.50 (d, J=11.87 Hz, 1 H), 4.55(d, J=11.87 Hz, 1H), 6.7 (d, 1H, J=2.6 Hz), 6.8-7.0 (m, 4H), 7.1-7.2 (m,2H), 7.28-7.33 (m, 6H).

EXAMPLE 1514-{[4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4S-cyclohexyl-butyryl]-methyl-amino}-S,R-cyclohexanecarboxylicacid amide

Step A:

To a stirred solution of4-{[4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4S-cyclohexyl-butyryl]-methyl-amino}-S,R-cyclohexanecarboxylicacid (1.51 g, 2.3 mmol) and triethylamine (0.95 mL, 6.8 mmol) indichloromethane (50 mL), di-tert-butyl dicarbonate (1.25 g, 5.7 mmol)was added. The reaction mixture was then stirred at room temperatureovernight. N,N-diisopropylethylamine (1.0 mL, 5.8 mmol) was added. Thereaction mixture was stirred for another 48 h at room temperature.Dichloromethane (50 mL) was added. The reaction mixture was washed withaqueous hydrochloric acid (1.0 M) twice and water one time, then driedover magnesium sulfate. The solution was filtered and concentrated toyield a white solid. The solid was dissolved in THF (20 mL). Sodiumhydroxide (1 N, 3.8 mL, 3.8 mmol) was added. The solution was stirred atroom temperature overnight. The solution was acidified to pH 4 by addingaqueous hydrochloric acid solution (1.0 N). The solution was extractedwith ethyl acetate twice. The combined ethyl acetate extracts werewashed with water and dried over magnesium sulfate. The solution wasfiltered and concentrated to yield4-{[4-(2-tert-butoxycarbonylamino-6-phenoxy-4H-quinazolin-3-yl)-4S-cyclohexyl-butyryl]-methyl-amino)-S,R-cyclohexanecarboxylicacid as a white solid.

MH⁺=647.4.

Step B:

To a stirred solution of the white solid isolated in Step A (0.104 g,0.16 mmole), ammonium chloride (0.017 g, 0.32 mmole), andN,N-diisopropylethylamine (0.08 mL, 0.48 mmole) in DMF (1.0 mL), HBTU(0.073 g, 0.19 mmole) was added. After stirring at room temperatureovernight, the reaction mixture was diluted with diethyl ether (3.0 mL).The reaction mmixture was extracted with aqueous hydrochloric acid (1.0N) twice, water one time, and dried over sodium sulfate. The reactionmixture was filtered and concentrated to a residue. The residue wasdissolved in dichloromethane (1.0 mL). Trifluoacetic acid (1.0 mL) wasadded. The reasulting solution was stirred at room temperature for 1hour. The solution was then concentrated to a residue. The residue waspurified by HPLC to yield4-{[4-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-4S-cyclohexyl-butyryl]-methyl-amino}-S,R-cyclohexanecarboxylicacid amide as a white solid.

MH⁺=546.7.

¹H NMR (300 MHz, DMSO) δ7.83 (s, 1H), 7.39 (m, 1H), 6.90-7.20 (m, 5H),6.74 (m, 1H), 4.30-4.47 (m, 2H), 3.50-3.90 (broad m, 3H), 2.00-2.40 (m,5H), 1.00-2.00 (m, 21H).

EXAMPLE 1524-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4S,N-dicyclohexyl-N-(1H-tetrazol-5-ylmethyl)-butyramide

Step A:

To a stirred solution of N-phthaloylglycine (11.92 g, 58 mmol) indichloromethane (200 mL) at room temperature, oxalyl chloride (7.5 mL,87 mmol) was added. DMF (two drops) was then added. The resultingsolution was concentrated after stirring four hours at room temperature.Dichloromethane (100 mL, dry) was then added to the residue. Benzylamine(9.5 mL, 87 mmol) was added slowly into the resulting solution.Triethylamine (12 mL, 87 mmol) was then added slowly into the solution.Dichloromethane (200 mL) and methanol (50 mL) were added 30 min afterthe completed addition of triethylamine. The resulting solution wasextracted with 2 N HCl solution twice, 1 N NaOH solution one time and 1N HCl one time, and then dried over MgSO₄. The solution was filtered andconcentrated to yieldN-benzyl-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetamide as a whitesolid.

MH⁺=294.9.

Step B:

Dissolution of the white solid isolated in Step A (8.02 g, 27.2 mmol) inacetonitrile (100 mL) was achieved by heating to reflux. After thesolution was cooled to 0° C., NaN₃ (2.30 g, 35.4 mmol) andtrifluoromethanesulfonic anhydride (10 g, 35.4 mmol) were added. Theresulting solution was then stirred at room temperature overnight.Dichloromethane (200 mL) was added. The resulting solution was washedwith saturated sodium bicarbonate solution three times and brine onetime and then dried over MgSO₄. The solution was filtered andconcentrated to yield2-(1-benzyl-1H-tetrazol-5-ylmethyl)-isoindole-1,3-dione as a whitesolid.

MH⁺=320.0.

Step C:

To a stirred solution of the solid isolated in Step B (7.88 g, 24.7mmol) in ethanol (300 mL), hydrazine (1.58 g, 49.3 mmol) was added. Thereaction mixture was then refluxed four hours. After cooling down toroom temperature, the white solid from the solution was removed byfiltration. The filtrate was concentrated. Acetonitrile (50 mL) wasadded to the residue. The precipitate from the solution was removed byfiltration. The filtrate was concentrated to yield a colorless oil whichwas treated with 1 N HCl in diethyl ether to yieldC-(1-benzyl-1H-tetrazol-5-yl)-methylamine as a white solid, as itscorresponding HCl salt.

MH⁺=190.1.

Step D:

To a stirred solution of the solid isolated in Step C (3.27 g, 14.5mmol) in methanol (100 mL), sodium acetate (1.43 g, 17.4 mmol) andcyclohexanone (1.65 mL, 15.9 mmol) were added. The resulting solutionwas concentrated, and then THF (50 mL) and dichloromethane (50 mL) wereadded. The solution was cooled to 0° C., and sodiumtriacetoxyborohydride (6.14 g, 29 mmol) was added. The resultingsolution was stirred at this temperature for six hours and then at roomtemperature for six hours. The reaction mixture was concentrated to aresidue. The residue was dissolved in 1 N hydrochloric acid solution (50mL). The resulting solution was extracted with diethyl ether once.Sodium bicarbonate was added slowly into the aqueous solution until nomore bubbling from the solution was observed. The solution was extractedwith ethyl acetate three times. The combined ethyl acetate extracts weredried over MgSO₄. The solution was concentrated to yield(1-benzyl-1H-tetrazol-5-ylmethyl)-cyclohexyl-amine as a colorless oil.

MH⁺=272.1.

Step E:

To a stirred solution of 4-tert-butoxycarbonylamino-4-cyclohexyl-butyricacid (2.63 g, 9.2 mmole), the oil isolated in Step D (2.50 g, 9.2mmole), and N,N-diisopropylethylamine (3.2 mL, 18.4 mmole) in DMF (50mL), HBTU (4.19 g, 11.0 mmole) was added. After stirring at roomtemperature overnight, the solution was diluted with diethyl ether (200mL). The solution was extracted with water three times and dried overmagnesium sulfate. The solution was then concentrated to yield{3-[(1-benzyl-1H-tetrazol-5-ylmethyl)-cyclohexyl-carbamoyl]-1S-cyclohexyl-propyl}-carbamicacid tert-butyl ester as a colorless oil.

MH⁺=539.2.

Step F:

To a stirred solution of the oil isolated in Step E (2.34 g, 4.3.mmol)in THF (50 mL) and ethanol (50 mL), Pd(OH)₂ (3.25 g, 20% on carbon) wasadded. The solution was hydrogenated at 50 psi at room temperature forfive hours. The solution was filtered and concentrated to yield a whitesolid. MH⁺=449.0. To a solution of the white solid. (1.29 g, 2.9 mmole)in dichloromethane (21 mL) was added trifluoroacetic acid (21 mL). Theresulting solution was stirred at room temperature for 1 hour and thenconcentrated to yield4-amino-4S,N-dicyclohexyl-N-(1H-tetrazol-5-ylmethyl)-butyramide as aresidue as its corresponding TFA salt.

Step G:

To a stirred solution of the material isolated in Step G (0.66 g) inmethanol (30 mL), 2-nitro-5-phenoxy-benzaldehyde (0.318 g, 1.3 mmole),and sodium acetate (0.32 g, 3.9 mmol) were added. The resulting solutionwas concentrated to dryness. Dichloromethane (30 mL), THF (30 mL) and 4Å molecular sieves (4 g) were added. After stirring at room temperaturefor 1 h, the resulting solution was cooled to 0° C. Sodiumtriacetoxyborohydride (0.55 g, 2.6 mmol) was added slowly into thesolution. The solution was stirred at 0° C. for 8 h and then warmed toroom temperature overnight. Diethyl ether (200 mL) was added. Theresulting solution was filtered and extracted with saturated sodiumbicarbonate solution three times and dried over magnesium sulfate. Thesolution was filtered and concentrated to yield4S,N-dicyclohexyl-4-(2-nitro-5-phenoxy-benzylamino)-N-(1H-tetrazol-5-ylmethyl)-butyramideas a slightly colored oil.

MH⁺=575.8.

Step H:

To a solution of the oil isolated in Step H (0.35 g, 0.6 mmole) inethanol (20 mL) and THF (20 mL), 10% palladium on carbon (0.27 g) wasadded. The resulting solution was subjected to hydrogenation for 1 hourat 20 psi. The resulting solution was filtered. Cyanogen bromide (3 M indichloromethane, 0.30 mL, 0.9 mmole) was added. The solution was stirredat room temperature overnight. The solution was then concentrated to aresidue. The residue was purified by HPLC to yiled4-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-4S,N-dicyclohexyl-N-(1H-tetrazol-5-ylmethyl)-butyramideas a white solid, as its corresponding TFA salt.

MH⁺=570.9

¹H NMR (300 MHz, DMSO), δ7.85 (s, 2H), 6.73-7.41 (m, 8H), 4.63 (s, 2H),4.35-4.50 (m, 2H), 3.79-3.82 (m, 2H), 2.00-2.45 (m, 3H), 1.00-2.00 (m,23H).

EXAMPLE 153{[4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4S-cyclohexyl-butyryl]-cyclohexyl-amino}-aceticacid

Step A:

Following the procedure of Example 152, Step D, except substitutingaminoacetonitrile hydrochloride salt for the product of Example 152,Step C, cyclohexylamino-acetonitrile, as a white solid was prepared.

MH⁺=139.1.

Step B:

Following the procedure of Example 152, Step E, except substituting theproduct of Example 153, Step A, for the product of Example 152, Step D,[3-(cyanomethyl-cyclohexyl-carbamoyl)-1S-cyclohexyl-propyl]-carbamicacid tert-butyl ester as a slightly colored oil was prepared.

MH⁺=406.4.

Step C:

To a stirred solution of the oil isolated In Step B (6.10 g, 15.0 mmole)in dichloromethane (20 mL), trifluoroacetic acid (20 mL) was added. Theresulting solution was stirred at room temperature for 2 h. The solutionwas then concentrated. Hydrochloric acid solution (1 N, 10 mL) was addedto the residue. The resulting solution was extracted with diethyl etherone time. Sodium bicarbonate was added until there was no more bubblingobserved from the aqueous solution. The aqueous solution was extractedwith ethyl acetate three times. The combined ethyl acetate extracts weredried over magnesium sulfate. The resutling solution was filtered andconcentrated to yield[(4-amino-4S-cyclohexyl-butyryl)-cyclohexyl-amino]-acetic acid as a greysolid.

MH⁺=324.0

Step D:

To a stirred solution of the solid isolated in Step C (3.40 g, 10.5mmole), 2-nitro-5-phenoxy-benzaldehyde (2.71 g, 11.1 mmole) in THF (20mL), dichloromethane (40 mL) and 4 Å molecular sieves (6 g) were added.After stirring at room temperature for 1 h, the solution was cooled to0° C. Sodium triacetoxy-borohydride (4.72 g, 22.3 mmol) was added slowlyinto the solution. The resulting solution was stirred at 0° C. for 8 hand then warmed to room temperature overnight. Diethyl ether (200 mL)was added. The resulting solution was filtered through a pad of Celite.The filtrate was extracted with 1 N HCl solution three times. Thecombined aqueous HCl extracts were neutralized by adding solid sodiumbicarbonate. The aqueous solution was extracted with ethyl acetatetwice. The combined ethyl acetate extracts were dried over magnesiumsulfate. The solution was filtered and concentrated to yield{cyclohexyl-[4-Scyclohexyl-4-(2-nitro-5-phenoxy-benzylamino)-butyryl]-amino)-aceticacid as a slightly colored oil.

MH⁺=551.0.

Step E:

Following the procedure of Example 152, Step H, except substituting theproduct of Step D above for the product of Example 152, Step G,([4-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-4S-cyclohexyl-butyryl]-cyclohexyl-amino)-aceticacid was prepared as a white solid.

MH⁺=546.0

¹H NMR (300 MHz, DMSO), δ10.80 (s, 1H), 7.91 (s, 1H), 6.96-7.47 (m, 8H),4.35-4.50 (m, 2H), 3.81-3.87 (m, 3H), 2.00-2.45 (m, 5H), 1.00-2.00 (m,23H).

EXAMPLE 1543-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-N-(4-cyano-cyclohexyl)-3S-cyclohexyl-N-methyl-propionamide

Step A:

To a stirred solution of Boc-D-cyclohexylglycine (4.25 g, 16.5 mmol) andtriethyl amine (2.7 ml, 19.8 mmol) in THF (100 mL) at 0° C., ethylchloroformate was added. The resulting solution was stirred at thistemperature for 1 hr. Diazomethane in diethyl ether, freshly preparedfrom N-methyl-N-nitrosourea (6.0 g, 58.2 mmol), was added slowly intothe solution. The solution was stirred at 0° C. for two hours and thenat room temperature overnight. Ethyl acetate (100 mL) was added. Thesolution was washed with aqueous hydrochloric acid (1.0 N) once,saturated sodium bicarbonate solution once, and then was dried overmagnesium sulfate. The solution was filtered and concentrated to yield awhite solid.

¹H NMR (300 MHz, CDCl₃), δ5.40 (br s, 1H), 5.12 (br m, 1H), 4.04 (br m,1H), 0.98-1.76 (m, 11H), 1.43 (s, 9H).

Step B

To a stirred solution of the white solid (4.99 g, 17.6 mmol) isolated inStep A in a solvent mixture of THF (100 mL) and water (10 mL) at 0° C.,silver trifluoroacetate (0.78 g, 3.5 mmol) in triethyl amine (7.3 mL,52.7 mmol) was added. The resulting solution was stirred at roomtemperature in the dark for four hours. Diethyl ether (100 mL) was thenadded. The resulting solution was extracted with aqueous sodiumhydroxide (1.0 N) three times. The combined aqueous phases wereacidified with 2 N HCl solution. The resulting solution was extractedwith ethyl acetate three times. The combined ethyl acetate extracts weredried over magnesium sulfate. The solution was filtered and concentratedto yield 3-tert-butoxycarbonylamino-3-cyclohexyl-propionic acid as aslightly colored solid.

¹H NMR (300 MHz, CDCl₃), δ5.63 (broad s, 1H), 3.74 (broad m, 1H), 2.57(broad m, 2H), 0.98-1.76 (m, 11H), 1.44 (s, 9H).

Step C:

Following the procedure of Example 152, Step E, except substituting thesolid from Step B above for4-tert-butoxycarbonylamino-4-cyclohexyl-butyric acid andN-(4-cyanocyclohexyl), N-methylamine hydrochloride for the oil isolatedin Example 152, Step D, a slightly colored oil was obtained.

MH⁺=292.0

Following Example 153, Step C, except substituting the slightly coloredoil for the solid isolated in Example 153, Step B,3-amino-N-(4-cyano-cyclohexyl)-3S-cyclohexyl-N-methyl-propionamide wasprepared as a slightly colored oil.

Step D:

Following the procedure of Example 153, Step D, except substituting theoil isolated in Step C above for the solid isolated in Example 153, StepC, (1.63 g, 89%)N-(4-cyano-cyclohexyl)-3S-cyclohexyl-N-methyl-3-(2-nitro-5-phenoxy-benzylamino)-propionamidewas prepared as a slightly colored solid.

¹H NMR (300 MHz, CDCl₃), δ8.14 (m, 1H), 6.90-7.50 (m, 7H), 4.96 (s, 2H),2.89 (s, 3H), 2.50-2.83 (m, 3H), 2.07 (m, 2H), 1.08-1.79 (m, 15H).

Step E:

Following the procedure of Example 152, Step H, except substituting theoil isolated in Step D above for the oil isolated in Example 152, StepG,3-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-N-(4-cyano-cyclohexyl)-3S-cyclohexyl-N-methyl-propionamidewas prepared as a white solid.

MH⁺=513.9

¹H NMR (300 MHz, DMSO), δ8.00 (broad s, 2H), 6.89-7.43 (m, 8H),4.09-4.51 (m, 3H), 2.77 (s, 3H), 2.60-2.95 (m, 4H), 1.00-2.00 (m, 19H).

EXAMPLE 1551-[4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4S-cyclohexyl-butyryl]-octahydro-indole-2S-carboxylicacid

Step A:

To a stirred solution of Boc-L-octahydroindole-2S-carboxylic acid (0.98g, 3.64 mmol) in a solvent mixture of dichloromethane (20 mL) andmethanol (3.0 mL) at 0° C., (trimethylsilyl)diazomethane (2.0 M inhexane, 5.5 mL, 10.9 mmol) was added. The resulting solution was stirredat room temperature for two hours. The solution was then concentrated toa residue. The residue was dissolved in dichloromethane (11 mL). TFA (11mL) was then added. The resulting solution was stirred at roomtemperature for one hour. The solution was then concentrated. Water (20mL) was added followed by excess solid sodium bicarbonate. The resultingsolution was extracted with ethyl acetate three times. The combinedorganic extracts were dried over magnesium sulfate. The solution wasfiltered and concentrated to yield octahydro-indole-2S-carboxylic acidmethyl ester as a colorless oil.

MH⁺=184.1

Step B:

Following the procedure of Example 152, Step E, except substituting theoil isolated in Step A above for the oil isolated in Example 152, StepD,1-(4-tert-butoxycarbonylamino-4-cyclohexyl-butyryl)-octahydro-indole-2S-carboxylicacid methyl ester was prepared as a slightly colored oil.

MH⁺=450.9.

Step C:

Following the procedure of Example 153, Step C, except substituting theoil isolated in Step B above for the oil isolated in Example 153, StepB, 1-(4-amino-4-cyclohexyl-butyryl)-octahydro-indole-2S-carboxylic acidmethyl ester was prepared as a grey solid.

MH⁺=351.2

Step D:

Following the procedure of Example 153, Step D substituting the solidisolated in Step C above for the solid isolated in Example 3, Step C,1-[4-S-cyclohexyl-4-(2-nitro-5-phenoxy-benzylamino)-butyryl]-octahydro-indole-2S-carboxylicacid methyl ester was prepared as a slightly colored oil.

MH⁺=578.2.

Step E:

Following the procedure of Example 152, Step H, except substituting theoil isolated in Step D above for the oil isolated in Example 152, StepG,1-[4-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-4S-cyclohexyl-butyryl]-octahydro-indole-2S-carboxylicacid methyl ester was prepared as a white solid.

MH⁺=573.3.

Step F:

To a stirring solution of the solid isolated in Step E (0.1365 g, 0.20mmol) in a solvent mixture of THF (1.0 mL) and methanol (1.0 mL),aqueous sodium hydroxide solution (1.0 M, 0.6 mL, 0.60 mmol) was added.The resulting solution was stirred at room temperature for three hours.The solution was then acidified with aqueous hydrochloric acid (2.0 M).The solution was purified by HPLC to yield1-[4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4S-cyclohexyl-butyryl]-octahydro-indole-2S-carboxylicacid as a white solid.

MH⁺=559.3

¹H NMR (300 MHz, DMSO) δ10.96 (s, 1H), 8.03 (s, 2H), 7.34-7.62 (m, 2H),6.95-7.23 (m, 6H), 4.10-4.50 (m, 3H), 3.71-3.81 (m, 1H), 3.05-3.09 (m,1H), 0.73-2.34 (m, 28H).

EXAMPLE 1564-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4S,N-dicyclohexyl-N-[2R-(3R,4S,5S-trihydroxy-6R-hydroxymethyl-tetrahydro-pyran-2-yloxy)-ethyl]-butyramide

Step A:

2-Cyclohexylamino-ethanol (11.6 g, 81 mmol) was taken into a mixture of1:1 dioxane:water (200 mL), and sodium carbonate (8.6 g, 81 mmol) wasthen added. The resulting solution was cooled with an ice bath andBoc-anhydride (18.6 mL, 81 mmol) in dioxane (50 mL) was added. Thereaction mixture was stirred at room temperature overnight, and then wasquenched with water and extracted with ethyl acetate. The organic layerwas washed with 1N HCl, saturated NaHCO₃, and brine and then was driedover sodium sulfate. The solvent was removed in vacuo to yield a clearoil.

¹H NMR (300 MHz, DMSO): δ1.0-1.3 (m, 4H), 1.4 (s, 9H), 1.45-1.8 (m, 6H),3.1 (s, 2H), 3.4 (m, 2H), 3.7 (s, 1H), 4.6 (m, 1H).

Step B:

The oil from Step A (4.67 g, 19.2 mmol) and β-D-glucose pentaacetate (15g, 38 mmol) were taken up in dry DCM (50 mL). The reaction mixture wascooled with an ice bath and boron trifluoride-diethyl etherate (23.86mL, 190 mmol) was added slowly. The reaction mixture was stirred at roomtemperature overnight. The reaction was complete, and the Boc group hadbeen removed. The reaction mixture was poured into ice water andextracted with DCM. The DCM extracts were combined and washed with coldsaturated NaHCO₃ and brine and then was dried over sodium sulfate. Thesolvent was removed in vacuo to yield a residue which was purified onnormal phase column with 95/5 DCM/MeOH to yield an oil.

¹H NMR (300 MHz, CDCl₃): δ1.0-1.3 (m, 5H), 1.6-1.9 (m, 6H), 1.95 (s,3H), 1.98 (s, 3H), 2.05 (s, 3H), 2.1 (s, 3H), 2.38 (m, 1H), 2.75 (m,2H), 3.64 (m, 2H), 3.94 (m, 1H), 4.12 (m, 1H), 4.26 (m, 1H), 4.55 (d,1H), 4.98 (t, 1H), 5.1 (t, 1H), 5.2 (t, 1H).

Step C:

To a solution of the oil from Step B (3.0 g, 6.3 mmol) in DMF (35 mL)was added 4-tert-butoxycarbonylamino-4-cyclohexyl-butyric acid (1.85 g,6.3 mmol), HOBt (1.06 g, 7.9 mmol), EDC (1.5 g, 7.9 mmol) and DIPEA (1.6mL, 9.5 mmol). The reaction mixture was stirred at room temperatureovernight. The reaction was quenched with water, and the reactionmixture was extracted with ethyl acetate. The ethyl actate extract waswashed with saturated NaHCO₃ and brine and then was dried over sodiumsulfate. The solvent was evaporated, and the residue was purified on anormal phase column with 95/5 DCM/MeOH to yield a light yellow oil.

MH⁺741.0

Step D:

The oil from Step C (2.0 g, 2.7 mmol) was taken into DCM (20 mL) andthen TFA (10 mL) was added. The reaction mixture was stirred for 2 hoursat room temperature. The reaction mixture was quenched with saturatedNaHCO₃ and extracted with ethyl acetate. The ethyl acetate extract waswashed with brine and dried over sodium sulfate. The solvent was removedin vacuo to yield a residue which was used in the next step withoutfurther purification.

MH⁺641.0

Step E:

The product from Step D (1.0 g, 1.56 mmol) and2-nitro-5-phenoxy-benzaldehyde (0.42 g, 1.56 mmol) were taken intomethanol (20 mL) and stirred at room temperature overnight. The reactionmixture was cooled with an ice bath. A sodium borohydride pellet (0.18g, 4.8 mmol) was added, and the reaction mixture effervesced. After 1 h,the reaction was quenched with acetic acid to neutral pH. Ethyl acetatewas added, and the resulting solution was washed with saturated solutionNaHCO₃ and brine and then dried over sodium sulfate. The solvent wasremoved in vacuo to yield a residue which was purified on a normal phasecolumn with 98/2 DCM/MeOH to yield a residue.

MH⁺867.9

Step F:

The residue from E (0.5 g, 0.57 mmol) was taken into ethanol (15 mL) and10% Pd/C (0.10 g) was added. The reaction mixture was stirred under H₂for 4 hours. The reaction mixture was then filtered through Celite. Thesolvent was removed to yield a residue as crude material.

MH⁺837.9

Step G:

The crude material from Step F (0.5 g, 0.57 mmol) was taken up inethanol (8 mL), and then 3M cyanogen bromide in DCM (0.288 mL, 0.86mmol) was added. The reaction mixture was stirred at 80° C. for 2.5hours. The reaction mixture was quenched with saturated NaHCO₃ solutionand then extracted with ethyl acetate. The organic extract was washedwith brine and dried over sodium sulfate. The solvent was removed invacuo to yield a residue which was purified on a normal phase columnwith 97.5/2.5 DCM/MeOH to yield a white solid.

MH⁺863.0

Step H:

To a solution of the white solid prepared in Step G (0.10 g, 0.12 mmol)in methanol (4 mL) was added hydrazine monohydrate (75 μL, 2.4 mmol).The reaction mixture was stirred at room temperature for 2.5 hours. Thesolvent was removed in vacuo, and the residue was purified on the HPLC.The desired fractions were made basic with saturated NaHCO₃ andextracted with ethyl acetate. The ethyl actate extracts were washed withbrine and dried over sodium sulfate. The solvent was removed in vacuo,and the residue was taken into isopropanol (4 mL) and 1N HCl was added,followed by addition of water (8 mL). The resulting solution was frozenand lyophilized to yield the title compound as a white powder.

MH⁺695.4

¹H NMR (300 MHz, CDCl₃): δ0.8-1.3 (m, 10H)p 1.32-1.75 (m, 12H), 1.8-2.8(m, 5H), 3.2-4.5 (m, 16H), 6.65 (s, 1H), 6.8 (m, 3H), 7.1 (m, 2H), 7.30(m, 2H), 7.9 (s, 2H), 10.6 (s, 1H)

EXAMPLE 157(3-{[4-(2-Amino-6-phenoxy-4H-quinazolin-3-yl)-4S-cyclohexyl-butyryl]-cyclohexyl-amino}-propyl)-carbamicacid 3R,4R,S5,6S-tetrahydroxy-tetrahydro-pyran-2R-ylmethyl ester

Step A:

Imidazole-1-carboxylic acid3,4,5,6-tetrakis-benzyloxy-tetrahydro-pyran-2-ylmethyl ester (0.114 g,0.18 mmol), synthesized according to the procedure disclosed in Org.Biomol. Chem., 2003, 1, 767-771, was taken up in THF (10 mL) under N₂.1,3-diaminopropane (0.067 mL, 0.72 mmol) and triethylamine (0.278 mL,1.8 mmol) were added, and the reaction mixture was stirred at roomtemperature for 1 hour. The reaction was quenched with water, and theresulting solution was extracted with ethyl acetate. The organic extractwas washed with water and brine and then dried over sodium sulfate,filtered, and concentrated in vacuo to yield a yellow oil which wastaken to the next step without further purification.

MH⁺641.0

Step B:

The yellow oil from Step A (0.10 g, 0.16 mmol) and cyclohexanone (0.032mL, 0.32 mmol) were taken up THF (10 mL). The reaction mixture was thenstirred at room temperature for 1 hour. Sodium triacetoxyborohydride(0.135 g, 0.64 mmol) was added, and the reaction mixture was stirred atroom temperature overnight. Ethyl acetate was added, and the resultingsolution was washed with saturated aqueous NaHCO₃ solution and brine,then dried over sodium sulfate, filtered, and concentrated in vacuo toyield an oil which was taken to the next step without furtherpurification.

MH⁺723.0

Step C:

To a solution of the oil from Step B (2.58 g, 3.6 mmol) in DMF (35 mL)was added (S)-4-t-butoxycarbonylamino-4-cyclohexylbutyric acid (1.27 g,4.5 mmol), HOBT (0.73 g 5.4 mmol), EDC (1.0 g, 5.4 mmol), and DIPEA(1.25 mL, 7.2 mmol). The reaction mixture was stirred at roomtemperature overnight. The reaction was quenched with water, and theresulting mixture was extracted with ethyl acetate. The organic extractwas washed with saturated aqueous NaHCO₃ and brine, then dried oversodium sulfate, filtered, concentrated and the residue purified on anormal phase column with 99:1 DCM:MeOH to yield a light yellow oil.

MH⁺989.9

Step D:

The oil from Step C (1.58 g, 0.16 mmol) was taken into DCM (20 mL) andthen TFA (10 mL) was added. The solution was stirred for 2 hours at roomtemperature and then quenched with saturated aqueous NaHCO₃. Theresulting mixture was extracted with ethyl acetate. The organic extractswere washed with brine, dried over sodium sulfate, filtered, andconcentrated in vacuo to yield crude product which was used in the nextstep without further purification.

MH⁺890.0

Step E:

The crude product from Step D (1.4 g, 1.6 mmol) and2-nitro-5-phenoxy-benzaldehyde (0.48 g, 2.0 mmol) were taken intomethanol (20 mL) and stirred at room temperature for 2 hours. A sodiumborohydride pellet (0.30 g, 6.7 mmol) was added, and the reaction wasobserved to effervesce. After 30 minutes, the reaction was quenched withwater. The resulting solution was extracted with ethyl acetate. Theorganic extract was washed with saturated aqueous NaHCO₃ and brine,dried over sodium sulfate, filtered, and concentrated in vacuo to yielda residue. The residue was purified on a normal phase column with 98:2DCM:MeOH to yield product.

MH⁺1116.8

Step F:

The product from Step E (0.35 g, 0.3 mmol) was taken into a 50:50ethanol/ethyl acetate solvent mixture (15 mL) and then 10% Pd/C (0.080g) was added. The reaction was stirred under a H₂ balloon for 1 hour.The solution was filtered through Celite. The filtrate was concentratedto yield crude product.

MH⁺1086.8

Step G:

The crude product from Step F (0.32 g, 0.3 mmol) was taken up intoethanol (4 mL) and then 3M cyanogen bromide in DCM (0.157 mL, 0.45 mmol)was added. The reaction was stirred at 80° C. for 2.5 hours. Thereaction was quenched with saturated aqueous NaHCO₃, and the resultingmixture was extracted with ethyl acetate. The organic extracts werewashed with brine, dried over sodium sulfate, filtered, and concentratedin vacuo to yield a residue. The residue was purified on a normal phasecolumn with 97.5:2.5 DCM:MeOH to yield product.

MH⁺1111.8

Step H:

The product from Step G (0.40 g, 0.36 mmol) was taken into a 4:3:3EtOAc:toluene:MeOH solvent mixture (20 mL) and-then 10% Pd/C (200 mg)was added. H₂ was added, and the reaction mixture was shaken under 50psi overnight. The catalyst was filtered off and solvent was removed invacuo. The reaction was repeated five more times. The catalyst wasfiltered off and solvent was removed in vacuo to yield a residue. Theresidue was purified by HPLC to yield the corresponding TFA salt, whichwas basified with saturated aqueous NaHCO₃ followed by addition of HClto yield the title compound as a white powder.

MH⁺752.0

¹H NMR (300 MHz, DMSO): δ 0.9-1.3 (m, 8H), 1.4-1.85 (m, 16H), 2.0-2.4(m, 3H), 2.85-3.6 (m, 13H), 3.75-4.5 (m, 5H), 4.85 (s, 1H), 6.97 (m,5H), 7.15 (t, 1H), 7.40 (t, 2H), 7.98 (s, 2H), 10.9 (m, 1H)

EXAMPLE 158 BACE Assay-1

The following standards are reagents were used in this assay: SodiumCitrate trisodium salt dihydrate (Sigma), Citric Acid monohydrate(Merck), PEG8000 (Sigma), MCA-substrate (Bachem), β-secretase (BACE)(Panvera), 96-well plate zwart (Costar (Elscolab)), StatVal (Bachem).

The following standard assay buffer solution was prepared and used inthis assay: 0.05 M, pH 5.0 mixture of sodium citrate trisodium saltdihydrate (9.56 g), citric acid monohydrate (3.68 g) and PEG8000 (0.50g).

The MCA-substrate stock solution was prepared by mixing 10 mgMCA-substrate with 5 mL DMSO for a final solution concentration of 2.0mg/mL. The substrate work solution was prepared by mixing 0.1 mLsubstrate in 1.90 mL assay buffer for a final concentration of 0.05 mM.The β-secretase (BACE) work solution was prepared by mixing 8 μL BACE in2 mL assay buffer for a final concentration of 10 g/mL.

Test compounds were dissolved in DMSO at various concentrations in therange of 3.3×10⁻³ M to 1.5×10⁻⁶ M.

The screen procedure for this assay was as follows. 60 μL of assaybuffer was pippeted into each well of a 96-well plate. To each well wasthen pipetted 1 μL of test compound at the selected concentration. Toeach well was then added 20 μL of the β-secretase work solution and 20ηL of the MCA-substrate stock solution. Each well was mixed for a fewsecond and the T₀ measured with fluoroscan Ex320/Em405. The plates werethen incubated for 1 hour at room temperature and the T60 measured withfluoroscan Ex320/Em405.

The procedure for the blank was as follows. 80 μL of assay buffer waspipetted into each well to be used as a blank control. To each well wasthen added 1 μL of DMSO and 20 μL of MCA-substrate solution in eachwell. The To was measured with fluoroscan Ex320/Em405, the plate wasincubated for 1 hour at room temperature and the T60 was then measuredwith fluoroscan Ex320/Em405.

The procedure for the positive control was as follows. 60 μL of assaybuffer was pipetted into each well to be used as a positive control. Toeach well was then added 1 μL of DMSO, 20 μL of BACE work solution and20 μL of MCA-substrate stock solution. The To was measured withfluoroscan Ex320/Em405, the plate was incubated for 1 hour at roomtemperature and the T60 was then measured with fluoroscan Ex320/Em405.

For test compounds, measured at multiple concentrations, the measured T₀and T₆₀ values were used to calculate an IC₅₀ value using GraphpadSoftware (or PIR).

EXAMPLE 159 BACE Assay-2

The following reagents were used in this assay: sodium acetate, PEG8000(Sigma), DMSO, HEPES, FS1 substrate [R(AedensE)EEVNLDAEFK-(DabcylK)R],β-secretase (BACE) (Panvera), and 96-well plate (HE microplate,Molecular Devices).

The following assay buffers were prepared and used in this assay: (1)enzyme assay buffer (0.05 M sodium acetate, pH 5, 0.1% PEG8000 (w/v)),(2) substrate assay buffer (0.05 M sodium acetate, pH 5), and (3)compound vehicle (30% DMSO in 50 mM HEPES, pH 7.4).

The FS1-substrate stock solution was prepared in DMSO as a 10 mg/mLsolution. The FS1-substrate working solution was prepared by dilutingthe 10 mg/mL stock solution with substrate assay buffer to a finalconcentration of 300 pg/mL. The β-secretase (BACE) working solution wasprepared by diluting a 0.83 mg/mL BACE stock solution with enzyme assaybuffer to a final concentration of 4 μg/mL.

Test compounds were dissolved in DMSO at 10 mM. Compounds were furtherdiluted in compound vehicle to various concentrations in the range of675 μM to 13.5 nM (13.5× final compound concentration in Ki plate).

The procedure for this assay was as follows: 15 μL of BACE workingsolution was pipetted into each well of a 96-well plate. To each wellwas then pipetted 2 μL of test compound at the selected concentration.Test compound and BACE were then mixed with a pipettor and incubated for20 min at room temperature. To each well was then added 10 μL of the FS1substrate working solution. The fluorescence for each well was thenmeasured on a Polarstar fluorometer (Ex 390 nm/Em 520 nm) for 20 min atroom temperature, reading fluorescence at 1 min intervals.

The procedure for the positive control was as follows:15 μL of BACEworking solution was pipetted into each well to be used as a positivecontrol. To each well was then pipetted 2 μL of vehicle. Vehicle andBACE were then mixed with a pipettor and incubated for 20 min at roomtemperature. To each well was then added 10 μL of the FS1 substrateworking solution. The fluorescence was then measured on a Polarstarfluorometer (Ex 390 nm/Em 520 nm) for 20 min at room temperature,reading fluorescence at 1 min intervals.

For test compounds, measured at multiple concentrations, the measured T₀and T₆₀ values were used to calculate an IC₅₀ value using GraphpadSoftware (or PIR). For test compounds, K_(i) inhibition was determinedas follows: For each compound concentration and positive control, rateof cleavage of substrate (V_(i), where i=compound concentration in μM)was determined as Δ Fluorescence/Δ time (min). Cleavage rates (V_(i))were plotted as a function of inhibitor concentration in μM [I]. TheK_(i) was then determined by fitting the following equation to the graphof [I] vs V_(i)Y=aV _(max)/(50+24*(1+X/K _(i))),

where 50=substrate concentration (μM) and 24=K_(m) of substrate (μM).

Representative compounds of the present invention were tested accordingto procedures described in Example 158 and 159 above with measured IC₅₀and K_(i) values as listed in Table 15 below. The procedure used todetermine a particular value is defined within the header row inparentheses (for example (158) indicates that the IC₅₀ values in thatcolumn were determined using the procedure described in Example 158).TABLE 15 BACE in vitro Assay Results IC₅₀ μM IC₅₀ μM Ki μM ID No. (158)(159) (159) 1 2.1 6.1 0.91 2 26 3 4.0 4 2.5 5 5.1 6 9.1 7 1.4 5.3 0.24 83.1 15 1.2 10 3.7 12 10 13 16 15 2.3 4.0 18 91 19 0.18 1.6 0.38 20 0.482.1 0.34 22 12 23 4.9 10 1.1 24 1.8 25 5.5 27 1.2 3.0 0.66 30 11 20 2.331 2.3 32 14 35 33 36 2.3 37 12 39 1.3 40 9.8 41 5.1 42 15 43 7.2 44 6.13.3 45 2.7 46 0.60 2.1 0.6 47 4.2 48 4.0 49 0.80 2.8 0.84 50 1 11 0.5351 2.2 13 1.2 53 1.0 6.8 0.82 54 2.3 55 0.28 2.4 0.79 56 0.97 5.4 0.7757 1.4 60 5.6 61 0.20 0.44 0.23 62 0.52 0.14 62 0.055 0.37 0.18 65 670.68 3.9 0.81 71 2.6 75 0.66 80 0.94 0.12 80 0.11 84 0.47 3.1 0.76 850.021 0.025 85 0.030 86 0.048 0.13 89 0.4 90 0.074 0.22 91 0.60 0.32 950.31 96 0.78 98 0.20 2.3 1.1 101 11 103 3.6 4.0 106 0.15 0.23 107 0.824.581 1.2 108 0.32 0.954 0.076 110 0.053 1.239 0.4 111 0.10 0 0.082 1110.067 112 0.12 0 0.59 113 0.99 114 0.079 0.27 121 0.58 0.32 122 0.190.17 123 1.2 0.3 126 0.24 127 0.16 0.18 128 0.072 0.13 129 0.10 0.12 1300.45 0.21 131 0.10 0.17 133 0.15 134 0.37 135 0.89 0.29 136 0.5 137 0.73138 0.023 0.06 140 0.32 141 0.15 0.08 148 0.25 149 0.21 150 0.46 1510.23 152 0.3 154 0.61 158 0.81 159 0.89 0.28 160 0.54 0.12 164 0.11 0.1165 0.19 0.28 167 0.03 167 0.014 0.05 169 0.058 0.08 170 0.77 173 0.47174 0.085 0.07 176 0.2 177 0.56 178 0.19 0.11 179 1.04 183 0.058 0.19192 0.22 196 0.015 0.11 199 0.51 201 0.4 203 4.7 204 0.062 0.23 205 0.32206 0.078 0.27 209 0.29 211 0.69 214 0.19 0.1 215 0.23 0.4 216 0.52 2180.13 0.1 219 0.31 0.17 220 0.45 0.2 221 0.023 0.025 221 0.011 0.029 2252.9 227 0.043 0.065 231 3.8 237 >10 238 8.9 239 0.35 240 0.89 241 0.49242 >10 243 0.033 244 2.1 245 0.17 246 >10 247 1.7 248 6.9 249 5.2250 >10 251 >10 252 1.0 253 >10 254 >10 255 >10 257 0.083 0.056 258 0.390.33 259 0.25 0.25 260 0.15 0.21 261 0.42 262 0.66 263 0.77 264 0.78 2651.1 268 0.65 269 0.35 270 2.37 271 0.39 272 0.52 273 0.17 274 >10275 >10 276 >10 277 0.70 278 >10 279 >10 280 11 281 1.6 282 >10 283 >10284 0.87 285 >10 288 >10 292 1.0 293 1.1 294 0.016 0.020 295 0.016 0.030296 0.90 297 0.066 0.12 298 0.22 0.23 301 0.15 0.21 302 0.050 0.14 3030.062 0.24 304 0.56 305 1.4 311 0.020 0.05 312 0.039 0.039 317 0.39 0.18318 0.25 0.19 319 0.053 0.074 322 0.14 0.29 324 0.52 325 0.089 0.1 3260.42 328 0.33 329 0.012 0.02 330 0.048 0.21 331 0.089 0.19 333 0.49 3340.068 335 0.24 340 2.0 342 0.082 0.19 343 0.041 0.065 344 0.058 3450.028 346 0.021 0.013 346 0.027 0.0082 346 0.021 0.012 353 0.35 355 2.6362 0.53 365 0.10 366 0.067 367 0.12 376 0.17 380 0.71 383 0.65 384 0.13385 0.28 386 0.033 386 0.41 0.17 387 3.3 388 0.063 389 0.028 390 0.57391 0.054 0.10 392 0.093 0.16 393 0.15 0.29 394 0.87 396 0.20 397 3.98404 0.78 418 0.035 419 0.29 421 0.054 423 5.8 424 0.40 425 0.14 0.074426 0.53 428 0.23 430 2.8 431 0.80 432 0.86 444 0.58 450 0.011 0.019 4641.3 476 0.067 0.28 484 1.1 0.74 485 0.012 0.017 487 0.36 0.26 487 0.36495 0.25 0.10 497 0.011 500 0.16 501 3.4 502 0.18 506 0.030 0.018 5060.030 0.0075 507 0.081 508 0.15 511 0.10 515 0.13 530 0.13 533 0.17 5340.18 535 0.076 536 0.086 537 0.041 538 0.44 545 0.14 556 0.044 558 0.16561 0.016 562 0.026 563 0.020 564 0.018 0.011 578 0.18 583 0.49 595 0.33601 0.027 602 0.056 603 0.033 605 0.54 610 0.076 618 0.19 619 0.011 6250.27 627 0.16 629 0.13 632 0.0084 634 0.054 635 0.014 638 0.23 647 0.033654 0.046 657 0.032 692 0.13 693 0.17 709 0.0065 710 0.30 711 0.45 7120.10 714 0.029 714 0.022 720 0.30 721 0.22 723 0.23 725 0.45 727 0.43728 0.38 729 0.33 730 0.054 731 0.087 732 0.010 736 0.013 739 0.005 7400.037 742 0.168 744 0.031 745 0.01 746 0.035 747 0.088 748 0.372 7490.017 750 0.005 751 0.025 752 0.221 753 0.656 755 0.21 1.9 0.270 7610.175 762 0.111 764 0.061 768 0.013 771 0.173 773 0.028 774 0.003 7760.107 779 0.045 781 0.038 782 0.015 783 0.301 784 0.298 785 0.198 7860.101 787 0.038 800 17

EXAMPLE 160 BACE FS1 % Inhibition Assay

The following reagents were used in this assay: sodium acetate, PEG8000(Sigma), DMSO, HEPES, FS1 substrate [R(AedensE)EEVNLDAEFK-(DabcylK)R],β-secretase (BACE) (Panvera), and 96-well plate (HE microplate,Molecular Devices).

The following assay buffers were prepared and used in this assay: (1)enzyme assay buffer (0.05 M sodium acetate, pH 5, 0.1% PEG8000 (w/v)),(2) substrate assay buffer (0.05 M sodium acetate, pH 5), and (3)compound vehicle (30% DMSO in 50 mM HEPES, pH 7.4).

The FS1-substrate stock solution was prepared in DMSO as a 10 mg/mLsolution. The FS1-substrate working solution was prepared by dilutingthe 10 mg/mL stock solution with substrate assay buffer to a finalconcentration of 300 μg/mL. The β-secretase (BACE) working solution wasprepared by diluting a 0.83 mg/mL BACE stock solution with enzyme assaybuffer to a final concentration of 4 μg/mL.

Test compounds were dissolved in DMSO to 10 mM. Compounds were furtherdiluted in vehicle to various concentrations in the range of 405 μM to4.05 μM (13.5× final compound concentration in screening plate).

The screening procedure for this assay was as follows: 15 μL of BACEworking solution was pipetted into each well of a 96-well plate. To eachwell was then pipetted 2 μL of test compound at the selectedconcentration. Test compound and BACE were then mixed with a pipettorand incubated for 20 min at room temperature. To each well was thenadded 10 μL of the FS1 substrate working solution. The plates were thenincubated for 1 hour at room temperature. The fluorescence for each wellwas then measured on an LJL analyst (Ex 360 nm/Em 530 nm).

The procedure for the blank was as follows. 15 μL of assay buffer waspipetted into each well to be used as a blank control. To each well wasthen added 2 μL of vehicle and 10 μL of FS1-substrate working solution.The plates were then incubated for 1 hour at room temperature. Thefluorescence was measured on an LJL analyst (Ex 360 nm/Em 530 nm).

The procedure for the positive control was as follows: 15 μL of BACEworking solution was pipetted into each well to be used as a positivecontrol. To each well was then pipetted 2 μL of vehicle. Vehicle andBACE were then mixed with a pipettor and incubated for 20 min at roomtemperature. To each well was then added 10 μL of the FS1 substrateworking solution. The plates were then incubated for 1 hour at roomtemperature. The fluorescence (Fl) was then measured on an LJL analyst(Ex 360 nm /Em 530 nm).

For test compounds, % inhibition was determined at each concentration asfollows:${\%\quad{Inhibition}} = \frac{\left\lbrack {{{Fl}\quad({compound})} - {{Fl}\quad\left( {{negative}\quad{control}} \right)}} \right\rbrack}{\left\lbrack {{{Fl}\quad\left( {{positive}\quad{control}} \right)} - {{Fl}\quad\left( {{negative}\quad{control}} \right)}} \right\rbrack}$

% Inhibition values of less than 30% were indistinguishable from controlare listed as <30% in the Table below. % Inhibition values greater than100% were indistinguishable from 100% within the error of themeasurement.

Representative compounds of the present invention were tested accordingto procedure described in Example 160 above with results as listed inTable 16 below. TABLE 16 % Inhibition (FS) ID No. 30 μM 10 μM 3 μM 1 μM0.3 μM 1 108 81 59 <30 <30 85 117 112 96 90 124 106 91 117 68 98 114 9349 105 <30 <30 <30 106 114 103 110 84 30 <30 114 126 109 115 105 40 11681 39 118 91 48 119 75 42 120 34 <30 121 117 103 122 123 101 123 116 71124 67 56 125 80 42 127 102 79 128 108 97 129 113 113 130 123 101 131130 115 132 118 54 134 104 70 135 118 89 136 133 85 137 107 82 138 114113 98 139 61 <30 140 101 79 141 102 100 142 38 <30 143 32 <30 144 59 39145 37 <30 146 39 <30 147 71 <30 148 114 62 35 149 111 71 32 150 90 <30<30 151 104 79 152 107 85 154 79 56 155 49 <30 156 40 <30 157 50 <30 15860 <30 <30 158 79 53 <30 159 92 65 34 160 102 78 51 161 <30 <30 <30 162<30 <30 <30 163 <30 33 <30 164 109 96 67 165 101 72 <30 166 74 37 <30167 113 112 100 167 118 110 91 168 <30 <30 <30 169 109 104 80 170 67 49<30 171 42 31 <30 172 <30 <30 <30 173 76 53 <30 174 111 106 85 175 37<30 <30 176 111 97 66 177 102 80 <30 178 107 93 50 179 85 54 <30 180 77<30 <30 181 32 <30 <30 182 38 <30 <30 183 106 93 48 184 31 <30 <30 18739 <30 <30 188 <30 <30 <30 189 <30 <30 <30 190 101 86 51 191 88 46 <30192 110 92 38 193 67 34 <30 194 38 42 <30 195 <30 <30 <30 196 120 96 65197 32 <30 <30 198 <30 <30 <30 199 82 <30 <30 200 <30 <30 <30 201 66 <30<30 202 <30 <30 <30 204 107 66 <30 204 115 97 54 205 90 47 <30 206 10662 <30 207 108 90 48 208 67 <30 <30 209 103 58 <30 210 <30 <30 <30 21168 <30 <30 212 32 <30 <30 213 <30 <30 <30 214 101 70 <30 215 106 71 39216 91 45 <30 217 56 <30 <30 218 114 101 75 219 108 85 51 220 102 72 103221 118 115 100 221 121 119 110 222 <30 <30 <30 223 <30 <30 <30 224 <30<30 <30 226 54 <30 <30 227 116 109 86 228 40 49 <30 229 <30 35 <30 230<30 33 <30 231 75 71 <30 232 31 <30 <30 233 36 32 <30 234 43 57 <30 235<30 46 <30 236 49 37 <30 257 111 105 67 258 72 46 <30 259 97 66 <30 260112 86 53 261 110 87 51 262 95 63 39 263 92 60 20 264 92 63 26 265 92 55<30 266 <30 34 <30 267 38 39 <30 268 71 <30 <30 286 36 <30 <30 290 <30<30 <30 292 83 49 <30 293 81 44 <30 294 118 109 94 295 116 106 79 297109 76 <30 298 110 75 <30 299 <30 <30 <30 300 77 <30 <30 301 106 82 <30302 108 72 <30 303 109 70 <30 304 100 46 <30 306 46 <30 <30 307 <30 <30<30 310 57 <30 <30 311 118 108 74 312 115 103 74 313 31 <30 <30 314 8545 <30 315 33 <30 <30 316 <30 <30 <30 320 <30 <30 −31 321 <30 <30 −33322 95 <30 <30 323 45 <30 <30 324 87 55 <30 325 110 86 <30 326 79 35 <30327 48 <30 <30 328 92 61 <30 329 118 109 92 330 114 66 <30 331 108 60<30 332 <30 <30 <30 333 78 <30 <30 334 118 103 74 395 118 107 69 398 <30<30 <30 400 94 <30 <30 401 52 <30 <30 402 99 53 <30 403 66 <30 <30 40467 32 <30 405 118 106 43 406 50 <30 <30 407 48 <30 <30 408 95 34 <30 40972 <30 <30 410 50 39 <30 411 55 <30 <30 412 49 <30 <30 413 53 <30 <30414 27 <30 <30 415 63 <30 <30 416 −3 <30 <30 417 78 <30 <30 418 119 8954 419 109 64 38 420 53 <30 <30 421 111 71 <30 424 94 50 <30 425 111 8546 426 86 34 <30 427 62 26 <30 428 98 60 <30 429 <30 <30 <30 432 84 41<30 433 88 33 <30 434 <30 <30 <30 435 85 <30 <30 436 50 37 <30 437 38<30 <30 438 <30 <30 <30 439 <30 <30 <30 440 72 35 <30 441 48 29 <30 442101 58 <30 443 67 39 <30 444 30 <30 <30 450 121 112 97 451 <30 <30 <30452 78 42 <30 463 <30 <30 <30 465 <30 <30 <30 466 53 <30 <30 467 <30 <30<30 468 <30 <30 <30 469 <30 <30 <30 470 31 <30 <30 471 38 <30 <30 472<30 <30 <30 473 <30 <30 <30 474 <30 <30 <30 475 <30 <30 <30 476 102 6619.86 477 <30 <30 <30 478 46 <30 <30 479 81 <30 <30 480 38 <30 <30 48132 <30 <30 482 43 <30 <30 483 <30 <30 <30 484 62 <30 <30 485 123 112 100486 <30 <30 <30 487 93 44 38 487 95 32 <30 488 <30 <30 <30 490 <30 <30<30 491 44 <30 <30 491 <30 <30 <30 493 49 <30 <30 494 <30 <30 <30 495106 75 <30 499 <30 <30 <30 503 90 <30 <30 504 96 31 <30 506 128 115 106508 113 74 31 509 41 <30 <30 510 37 <30 <30 511 113 85 34 512 51 <30 <30513 <30 <30 <30 514 <30 <30 <30 515 110 66 41 516 <30 <30 <30 517 40 <30<30 518 <30 <30 <30 519 <30 <30 <30 520 33 <30 <30 521 <30 <30 <30 52279 <30 <30 523 58 <30 <30 524 44 <30 <30 525 70 <30 <30 526 98 36 <30527 51 <30 <30 528 41 <30 <30 529 66 <30 <30 530 118 80 <30 532 68 <30<30 534 126 103 54 535 116 86 57 536 118 83 61 537 125 106 83 538 100 53<30 539 <30 <30 <30 540 84 30 <30 541 <30 <30 <30 542 73 <30 <30 543 <30<30 <30 544 51 <30 32 545 118 77 55 549 71 30 <30 550 67 <30 <30 551 <30<30 <30 552 36 <30 <30 553 49 <30 <30 554 42 <30 <30 555 46 <30 <30 556126 118 103 557 <30 <30 <30 558 115 92 42 559 <30 <30 <30 561 125 118114 562 128 118 106 563 127 119 101 564 129 119 112 567 <30 <30 <30 568<30 <30 <30 569 <30 <30 <30 570 <30 <30 <30 571 <30 <30 <30 573 <30 <30<30 574 <30 <30 <30 575 <30 <30 <30 576 <30 <30 <30 577 <30 <30 <30 578<30 <30 <30 578 97 64 31 580 <30 <30 <30 582 <30 <30 <30 583 86 56 40584 56 <30 <30 586 59 <30 <30 587 <30 <30 <30 588 <30 <30 <30 589 <30<30 <30 590 <30 <30 <30 591 <30 <30 <30 592 <30 <30 <30 593 <30 <30 <30594 <30 <30 <30 595 104 70 32 596 <30 <30 <30 598 36 <30 <30 599 65 <30<30 600 41 <30 <30 601 121 115 105 602 121 113 78 603 122 114 101 605111 72 47 606 56 <30 <30 607 123 116 94 610 119 106 75 611 <30 36 <30612 <30 34 <30 613 <30 31 36 614 <30 <30 <30 615 <30 <30 <30 616 <30 <30<30 617 41 34 <30 618 104 70 <30 619 125 118 119 620 37 <30 <30 623 82<30 <30 624 78 38 <30 625 95 54 <30 626 56 <30 <30 627 105 75 39 628 32<30 <30 629 102 72 <30 630 48 <30 <30 631 48 <30 <30 632 117 118 115 63370 30 <30 634 114 88 46 635 119 115 104 636 30 <30 <30 637 73 <30 <30638 116 101 74 639 48 <30 <30 640 <30 <30 <30 641 48 <30 <30 642 96 6337 643 110 92 74 644 104 72 46 645 91 57 67 646 97 72 52 647 113 100 79648 104 74 39 649 95 65 34 650 112 94 72 651 96 51 <30 652 91 63 31 653101 82 46 654 111 102 83 655 104 79 45 656 104 87 56 657 111 103 88 658100 62 <30 659 100 69 43 660 105 86 63 661 106 98 68 662 109 97 66 663<30 <30 <30 664 <30 <30 <30 665 <30 <30 35 666 <30 <30 37 667 <30 <30 33668 <30 <30 <30 669 32 <30 <30 670 44 <30 <30 671 <30 30 <30 672 <30 <30<30 673 <30 <30 34 674 41 <30 36 675 <30 <30 35 676 44 <30 33 678 99 8851 679 103 99 78 680 90 75 42 681 103 100 67 682 97 77 39 683 102 86 64684 78 38 33 685 101 90 50 686 80 73 <30 687 87 50 <30 688 81 36 <30 689102 82 33 690 52 <30 <30 691 51 <30 <30 692 116 90 46 693 109 83 47 69484 <30 <30 695 54 <30 <30 696 104 72 <30 697 63 <30 <30 698 64 <30 <30699 93 64 31 700 85 36 <30 701 54 <30 <30 702 <30 <30 <30 703 83 46 <30704 <30 <30 <30 705 <30 <30 <30 706 <30 <30 <30 707 <30 <30 <30 709 139143 141 710 126 68 <30 711 113 43 <30 712 134 104 39 714 138 126 100 714138 129 98 716 72 <30 <30 717 72 39 33 718 114 30 <30 719 81 <30 31 720138 93 72 721 127 66 60 722 78 35 35 723 111 63 47 724 65 <30 38 725 12674 33 726 46 <30 <30 727 137 80 46 728 97 58 43 729 100 61 33 730 114109 93 731 132 114 56 732 133 135 135 736 135 134 125 737 97 34 22 73861 28 14 739 105 104 99 740 104 98 82 741 −25 −38 −48 742 101 63 17 743130 125 107 744 112 108 91 745 114 114 115 746 112 104 85 747 104 74 41748 97 71 20 749 115 112 113 750 116 114 115 751 116 112 112 752 109 8145 753 93 47 13 754 89 35 8 755 79 59 760 89 44 <30 761 112 91 51 762113 102 74 763 109 84 <30 764 116 110 87 765 97 56 <30 766 <30 <30 <30767 106 71 <30 768 126 120 122 769 107 61 <30 770 <30 <30 <30 771 105 7946 773 119 111 102 774 124 120 122 775 111 62 <30 776 117 95 41 777 12397 38 778 113 77 <30 779 120 107 102 780 109 97 69 781 121 109 106 782113 107 104 783 121 110 109 784 120 108 107 785 107 91 71 786 114 105 97787 121 109 108 788 118 114 110 789 106 99 80 801 <30 <30 <30 802 50 <30<30 803 <30 <30 <30 804 <30 <30 <30 805 <30 <30 <30 806 <30 <30 <30 807<30 <30 <30 808 <30 <30 <30 809 32 <30 <30 810 <30 <30 <30 811 <30 <30<30

EXAMPLE 161 BACE % Inhibition Assay

The following reagents were used in this assay: sodium acetate, PEG8000(Sigma), DMSO, HEPES, (Aedens)-EVNLDAEF-(Dabcyl K-amide) substrate,β-secretase (BACE) (Panvera), and 96-well plate (HE microplate,Molecular Devices).

The following assay buffers were prepared and used in this assay: (1)enzyme assay buffer (0.05 M sodium acetate, pH 5, 0.1% PEG8000 (w/v)),(2) substrate assay buffer (0.05 M sodium acetate, pH 5), and (3)compound vehicle (30% DMSO in 50 mM HEPES, pH 7.4).

The substrate stock solution was prepared in DMSO as a 10 mg/mLsolution. The substrate working solution was prepared by diluting the 10mg/mL stock solution with substrate assay buffer to a finalconcentration of 300 pg/mL. The β-secretase (BACE) working solution wasprepared by diluting a 0.83 mg/mL BACE stock solution with enzyme assaybuffer to a final concentration of 4 μg/mL.

Test compounds were dissolved in DMSO to 10 mM. Compounds were furtherdiluted in vehicle to various concentrations in the range of 405 μM to4.05 μM (13.5× final compound concentration in screening plate).

The screening procedure for this assay was as follows: 15 μL of BACEworking solution was pipetted into each well of a 96-well plate. To eachwell was then pipetted 2 μL of test compound at the selectedconcentration. Test compound and BACE were then mixed with a pipettorand incubated for 20 min at room temperature. To each well was thenadded 10 μL of the substrate working solution. The plates were thenincubated for 1 hour at room temperature. The fluorescence for each wellwas then measured on an LJL analyst (Ex 360 nm/Em 530 nm).

The procedure for the blank was as follows. 15 μL of assay buffer waspipetted into each well to be used as a blank control. To each well wasthen added 2 μL of vehicle and 10 μL of substrate working solution. Theplates were then incubated for 1 hour at room temperature. Thefluorescence was measured on an LJL analyst (Ex 360 nm/Em 530 nm).

The procedure for the positive control was as follows: 15 μl of BACEworking solution was pipetted into each well to be used as a positivecontrol. To each well was then pipetted 2 μL of vehicle. Vehicle andBACE were then mixed with a pipettor and incubated for 20 min at roomtemperature. To each well was then added 10 μL of the substrate workingsolution. The plates were the incubated for 1 hour at room temperature.The fluorescence (Fl) was then measured on an LJL analyst (Ex 360 nm/Em530 nm).

For test compounds, % inhibition was determined at each concentration asfollows:${\%\quad{Inhibition}} = \frac{\left\lbrack {{{Fl}\quad({compound})} - {{Fl}\quad\left( {{negative}\quad{control}} \right)}} \right\rbrack}{\left\lbrack {{{Fl}\quad\left( {{positive}\quad{control}} \right)} - {{Fl}\quad\left( {{negative}\quad{control}} \right)}} \right\rbrack}$

% Inhibition values of less than 30% were indistinguishable from controlare listed as ≦30% in the Table below.

Representative compounds of the present invention were tested accordingto procedure described in Example 161 above with results as listed inTable 17 below. The % error in the measurements was ±10%. TABLE 17 %Inhibition ID No. 30 μM 10 μM 3 μM 1 μM 0.3 μM 1 61 44 24 1 61 38 31 <307 87 76 15 69 42 19 92 67 20 83 68 23 76 47 27 81 63 30 48 32 44 31 <3046 82 66 49 90 56 50 34 <30 51 56 <30 53 82 34 55 95 62 56 79 35 61 8775 62 82 62 62 82 73 65 <30 <30 67 71 44 72 <30 <30 77 <30 <30 79 <30<30 80 80 61 81 <30 <30 84 63 38 85 93 81 86 80 72 87 <30 <30 88 <30 <3089 81 77 93 <30 <30 94 <30 <30 97 53 <30 98 99 76 100 <30 <30 101 64 45103 74 56 105 <30 <30 107 78 48 108 90 73 109 58 <30 110 96 75 111 94 84111 115 96 63 112 92 88 317 107 66 <30 318 103 70 32 319 120 95 61 336<30 <30 <30 337 <30 <30 <30 338 <30 <30 <30 339 <30 <30 <30 341 72 <30<30 342 119 93 50 343 118 101 81 346 126 121 110 346 123 122 115 365 11386 <30 366 119 113 64 367 111 80 <30 386 122 112 80 386 107 53 <30 388119 119 107 389 120 112 85 390 102 50 <30 391 115 93 35 392 120 116 75393 113 52 <30

EXAMPLE 162 BACE Assay (CEREP)

This assay was run by CEREP (Catalog Ref. 761-B, Reffered to SOP No.1C131; ERMOLIEFF, J., LOY, J. A., KOELSCH, G. and TANG, J., Proteolyticactivation of recombinant pro-memapsin 2 (pro-β-secretase) studied withnew fluorogenic substrates, Biochemistry, (2000) Vol. 39, p. 12450).

More specifically the assay, run at 50 μL in a 96 well plate, evaluatedthe effect of test compound on the activity of the human BACE-1quantified by measuring the formation of Mca-S-E-V-N-L-NH₂ fromMca-S-E-V-N-L-D-A-E-F-R-K(Dnp)-R-R-NH₂, using a recombinant enzyme.

The test compound, reference compound or water (control) were added to abuffer containing 0.09 M sodium acetate (pH 4.5) and 0.25 μg BACE-1.Compound interference with the fluorimetric detection method due toautofluorescence was then checked by measurements at the wavelengthsdefined to evaluate the enzyme activity. Thereafter, the reaction wasinitiated by adding 7.5 μM of the substrateMca-S-E-V-N-L-D-A-E-F-R-K(Dnp)-R-R-NH₂ and the mixture was incubated for60 min at 37° C. For control basal measurement, the substrate wasomitted from the reaction mixture. Immediately after the incubation, thefluorescence intensity emitted by the reaction product Mca-S-E-V-N-L-NH₂was measured at λex=320 nm and λem=405 nm using a microplate reader(Ultra, Tecan). The standard inhibitory reference compound was OM99-2,which was tested in each experiment at several concentrations to obtainan inhibition curve from which its IC₅₀ value was calculated.

Representative compounds of the present invention were tested accordingto procedure described in Example 162 above with results as listed inTable 18 below. TABLE 18 % Inhibition and IC₅₀ ID No. 1 μM 0.3 μM IC₅₀(μM) 62 0.38 154 >1.0 346 99 0.18 788 97 0.16 789 94 0.078 790 98 0.093795 98 0.15 796 97 0.19 797 95 0.12 798 95 0.074

EXAMPLE 163

As a specific embodiment of an oral composition, 100 mg of the Compound#346, prepared as in Example 22 is formulated with sufficient finelydivided lactose to provide a total amount of 580 to 590 mg to fill asize ◯ hard gel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A compound of formula (II)

wherein R⁰ is selected from the group consisting of hydrogen, methyl,and CF₃; R¹ is selected from the group consisting of hydrogen, hydroxy,methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxyand methyl-carbonyl; c is an integer from 0 to 1; A² is selected fromthe group consisting of C₁₋₄alkyl; wherein the C₁₋₄alkyl is optionallysubstituted with one or more R^(Y) substituents; wherein each R^(Y) isindependently selected from the group consisting of hydroxy, oxo,C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, amino substituted C₁₋₆alkyl,cycloalkyl, cycloalkyl-C₁₋₄alkyl-, biphenyl, aryl, C₁₋₄aralkyl,heteroaryl, heteroaryl-C₁₋₄alkyl-, heterocycloalkyl,heterocycloalkyl-C₁₋₄alkyl- or spiro-heterocyclyl; wherein thecycloalkyl, aryl, heteroaryl, heterocycloalkyl or spiro-heterocyclylgroup, whether alone or as part of a substituent group is optionallysubstituted with one or more substituents independently selected fromthe group consisting of fluoro, chloro, hydroxy, oxo, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, —C(O)O—(C₁₋₄alkyl), hydroxy substitutedC₁₋₄alkyl, fluoro substituted C₁₋₄alkyl, fluoro substituted C₁₋₄alkoxy,5-tetrazolyl or 1-(1,4-dihydro-tetrazol-5-one);

is selected from the group consisting of aryl, aryl-C₁₋₄alkyl,cycloalkyl, partially unsaturated carbocyclyl, heteroaryl,heterocycloalkyl and spiro-heterocyclyl; wherein the aryl, cycloalkyl,partially unsaturated carbocyclyl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl group, whether alone or as part of a substituentgroup, is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₄alkyl,C₁₋₄alkoxy, halogen substituted C₁₋₄alkyl, halogen substitutedC₁₋₄alkoxy, hydroxy substituted C₁₋₄alkyl, hydroxy, carboxy, cyano,nitro, amino, C₁₋₄alkylamino and di(C₁₋₄alkyl)amino; provided that whenc is 0, then

is other than aryl or heteroaryl; Q³ is selected from the groupconsisting of —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —OC(O)—, —C(O)—NR^(A),—NR^(A)—C(O)—, —C(S)—NR^(A), —SO₂—NR^(A), —SO—NR^(A), —OC(O)—NR^(A)—,—NR^(A)—C(O)O— and —O—SO₂—NR^(A)—; wherein each R^(A) is independentlyselected from the group consisting of hydrogen, C₁₋₈alkyl, hydroxysubstituted C₁₋₄alkyl, C₁₋₄aralkyloxy substituted C₁₋₄alkyl, cycloalkyl,aryl, heteroaryl, heterocycloalkyl, cycloalkyl-C₁ ₄alkyl-, C₁₋₄aralkyl,heteroaryl-C₁₋₄alkyl-, heterocycloalkyl-C₁₋₄alkyl- andspiro-heterocyclyl; wherein the cycloalkyl, aryl, heteroaryl,heterocycloalkyl or spiro-heterocyclyl, whether alone or as part of asubstituent group is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, oxo, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxy-carbonyl, nitro, cyano, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —SO₂—N(R^(C)R^(D)), 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one); wherein each R^(C) and R^(D) isindependently selected from the group consisting of hydrogen andC₁₋₄alkyl; R² is selected from the group consisting of C₁₋₈alkyl,cycloalkyl, aryl, biphenyl, partially unsaturated carbocyclyl,heteroaryl, heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl,partially unsaturated carbocyclyl-C₁₋₄alkyl-, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl; wherein theC₁₋₈alkyl, cycloalkyl, aryl, partially unsaturated carbocyclyl,heteroaryl, heterocycloalkyl or spiro-heterocyclyl, whether alone or aspart of a substituent group is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, oxo, carboxy, —C(O)—C₁₋₄alkyl, —C(O)—C₁₋₄aralkyl,—C(O)O—C₁₋₄alkyl, —C(O)O—C₁₋₄aralkyl, —C₁₋₄alkyl-C(O)O—C₁₋₄alkyl,—C₁₋₄alkyl-S—C₁₋₄alkyl, —C(O)—N(R^(L)R^(M)),—C₁₋₄alkyl-C(O)—N(R^(L)R^(M)), —NR^(L)—C(O)—C₁₋₄alkyl,—SO₂—N(R^(L)R^(M)), —C₁₋₄alkyl-SO₂—N(R^(L)R^(M)), C₁₋₆alkyl, fluorosubstituted C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, carboxysubstituted C₁₋₄alkyl, C₁₋₄alkoxy, —O—C₁₋₄aralkyl,—O-(tetrahydropyranyl), —NH—C(O)O—CH₂-(tetrahydropyranyl),—N(CH₃)—C(O)O—CH₂-(tetrahydropyranyl), nitro, cyano, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, phenyl, 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one); wherein the phenyl or tetrahydropyranylis optionally substituted with one or more substituent independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,C(O)O—C₁₋₄alkyl, C(O)—C₁₋₄alkyl, OC(O)—C₁₋₄alkyl,—C₁₋₄alkyl-OC(O)—C₁₋₄alkyl, —O—C₁₋₄aralkyl, C₁₋₄alkyl, fluorosubstituted C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, C₁₋₄alkoxy, nitro,cyano, amino, C₁₋₄alkylamino and di(C₁₋₄alkyl)amino; wherein each R^(L)and R^(M) is independently selected from the group consisting ofhydrogen and C₁₋₄alkyl; b is an integer from 0 to 1; L¹ is selected fromthe group consisting of —O—, —S(O)₀₋₂—, —NR^(N)—, —C(O)—, —C(S)—,—C₁₋₄alkyl-, -(hydroxy substituted C₁₋₄alkyl)- and —(C₂₋₄alkenyl)-;wherein R^(N) is selected from the group consisting of hydrogen andC₁₋₄alkyl; R³ is selected from the group consisting of C₁₋₆alkyl,C₂₋₆alkenyl, cycloalkyl, partially unsaturated carbocyclyl, aryl,biphenyl, heteroaryl, heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-,C₁₋₄aralkyl, heteroaryl-C₁₋₄alkyl-, heterocycloalkyl-C₁₋₄alkyl- andspiro-heterocyclyl; wherein the C₁₋₆alkyl, cycloalkyl, partiallyunsaturated carbocyclyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl, whether alone or as part of a substituent group isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, halogen substituted C₁₋₄alkyl,cyano substituted C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,halogen substituted C₁₋₄alkoxy, nitro, cyano, —R⁵, —O—R⁵, —S—R⁵,—SO₂—R⁵, —SO₂—NR^(P)—R⁵, —NR^(P)—SO₂—R⁵, —NH₂, —N(R^(P))—R⁵, —C(O)—R⁵,—C(O)—NH₂, —C(O)—NR^(P)—R⁵, —NR^(P)—C(O)—R⁵ and —NR^(P)—C(O)O—R⁵;wherein R⁵ is selected from the group consisting of C₁₋₄alkyl, aryl,C₁₋₄aralkyl, partially unsaturated carbocyclyl, cycloalkyl,cycloalkyl-C₁₋₄alkyl-, partially unsaturated carbocyclyl-C₁₋₄alkyl-,heteroaryl, heteroaryl-C₁₋₄alkyl-, heterocycloalkyl andheterocyclyl-C₁₋₄alkyl-; wherein the aryl, partially unsaturatedcarbocyclyl, cycloalkyl, heteroaryl or heterocycloalkyl, whether aloneor as part of a substituent group is optionally substituted with one ormore substituent independently selected from the group consisting ofC₁₋₄alkyl, C₁₋₄alkoxy, halogen, hydroxy, carboxy, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, cyano and nitro; wherein R^(P) is selected from thegroup consisting of hydrogen, C₁₋₈alkyl, hydroxy substituted C₁₋₄alkyl,C₁₋₄aralkyloxy substituted C₁₋₄alkyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl,heteroaryl-C₁₋₄alkyl-, heterocycloalkyl-C₁₋₄alkyl- andspiro-heterocyclyl; wherein the cycloalkyl, aryl, heteroaryl,heterocycloalkyl or spiro-heterocyclyl, whether alone or as part of asubstituent group is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, oxo, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxy-carbonyl, nitro, cyano, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —SO₂—N(R^(S)R^(T)), 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one); wherein each R^(S) and R^(T) isindependently selected from the group consisting of hydrogen andC₁₋₄alkyl; a is an integer form 0 to 3; each R¹⁰ is independentlyselected from the group consisting of hydroxy, halogen, C₁₋₄alkyl,C₁₋₄alkoxy, halogen substituted C₁₋₄alkyl, halogen substitutedC₁₋₄alkoxy, —C(O)—NR^(V)R^(W), —SO₂—NR^(V)R^(W), —C(O)—C₁₋₄alkyl and—SO₂—C₁₋₄alkyl; wherein each R^(V) and R^(W) is independently selectedfrom the group consisting of hydrogen and C₁₋₄alkyl; alternatively R^(V)and R^(W) are taken together with the N atom to which they are bound toform a 5 to 6 membered saturated, partially unsaturated or aromatic ringstructure; provided that the halogens on the halogen substitutedC₁₋₄alkyl or the halogen substituted C₁₋₄alkoxy are selected from thegroup consisting of chloro and fluoro; provided that when R⁰ ishydrogen, R¹ is hydrogen, A¹ is —CH₂-,

is phenyl, Q³ is —O—, R² is methyl, b is an integer selected from 0 to 1and L¹ is selected from —O—, —NH— or —N(CH₃)—, then R³ is other thanmethyl; or a pharmaceutically acceptable salt thereof.
 2. A compound asin claim 1 R⁰ is selected from the group consisting of hydrogen andmethyl; R¹ is selected from the group consisting of hydrogen, methyl,trifluoromethyl, methoxy and methylcarbonyl; c is an integer from 0 to1; A² is selected from the group consisting of C₁₋₄alkyl; wherein theC₁₋₄alkyl is optionally substituted with one to two R^(Y) substituents;wherein each R^(Y) is independently selected from the group consistingof hydroxy, C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, amino substitutedC₁₋₆alkyl, cycloalkyl, cycloalkyl-C₁₋₄alkyl-, aryl, C₁₋₄aralkyl,heteroaryl, heteroaryl-C₁₋₄alkyl-, heterocycloalkyl andheterocycloalkyl-C₁₋₄alkyl-; wherein the cycloalkyl, aryl, heteroaryl orheterocycloalkyl group, whether alone or as part of a substituent groupis optionally substituted with one or more substituents independentlyselected from the group consisting of fluoro, chloro, hydroxy, oxo,carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, —C(O)O—(C₁₋₄alkyl), hydroxy substitutedC₁₋₄alkyl, fluoro substituted C₁₋₄alkyl and fluoro substitutedC₁₋₄alkoxy;

is selected from the group consisting of aryl, aryl-C₁₋₄alkyl-,cycloalkyl, heteroaryl and heterocycloalkyl; wherein the aryl,cycloalkyl, heteroaryl or heterocycloalkyl group, whether alone or aspart of a substituent group, is optionally substituted with one to twosubstituents independently selected from the group consisting ofC₁₋₄alkyl, C₁₋₄alkoxy, halogen substituted C₁₋₄alkyl, halogensubstituted C₁₋₄alkoxy, hydroxy substituted C₁₋₄alkyl, hydroxy, carboxy,cyano, nitro, amino, C₁₋₄alkylamino and di(C₁₋₄alkyl)amino; providedthat when c is 0, then

is other than aryl or heteroaryl; Q³ is selected from the groupconsisting of —O—, —S—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)—NR^(A),—NR^(A)—C(O)— and —NR^(A)—C(O)O—; wherein each R^(A) is independentlyselected from the group consisting of hydrogen, C₁₋₈alkyl, hydroxysubstituted C₁₋₄alkyl, cycloalkyl, aryl, C₁₋₄aralkyl, heteroaryl andheterocycloalkyl; wherein the cycloalkyl, aryl, heteroaryl orheterocycloalkyl, whether alone or as part of a substituent group isoptionally substituted with one to two substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy-carbonyl, nitro, cyano, amino,C₁₋₄alkylamino and di(C₁₋₄alkyl)amino; R² is selected from the groupconsisting of C₁₋₈alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl,cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl, partially unsaturatedcarbocyclyl-C₁₋₄alkyl-, heteroaryl-C₁₋₄alkyl- andheterocycloalkyl-C₁₋₄alkyl-; wherein the C₁₋₈alkyl, cycloalkyl, aryl,heteroaryl, heterocycloalkyl or spiro-heterocyclyl, whether alone or aspart of a substituent group is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, carboxy, —C(O)—C₁₋₄alkyl, —C(O)—C₁₋₄aralkyl,—C(O)O—C₁₋₄alkyl, —C(O)O—C₁₋₄aralkyl, —C(O)—N(R^(L)R^(M)),—NR^(L)—C(O)—C₁₋₄alkyl, —SO₂—N(R^(L)R^(M)) C₁₋₆alkyl, fluoro substitutedC₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, carboxy substituted C₁₋₄alkyl,C₁₋₄alkoxy, nitro, cyano, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino andphenyl; wherein the phenyl is optionally substituted with one to twosubstituent independently selected from the group consisting of halogen,hydroxy, carboxy, —C(O)—C₁₋₄alkyl, C₁₋₄alkyl, fluoro substitutedC₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano, amino, C₁₋₄alkylamino anddi(C₁₋₄alkyl)amino; wherein each R^(L) and R^(M) is independentlyselected from the group consisting of hydrogen and C₁₋₄alkyl; b is aninteger selected from 0 to 1; L¹ is selected from the group consistingof —O—, —S(O)₀₋₂—, —NR^(N)—, —C₁₋₄alkyl-, -(hydroxy substitutedC₁₋₄alkyl)- and —(C₂₋₄alkenyl)-; wherein R^(N) is selected from thegroup consisting of hydrogen and C₁₋₄alkyl; R³ is selected from thegroup consisting of C₁₋₆alkyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl,heteroaryl-C₁₋₄alkyl- and heterocycloalkyl-C₁₋₄alkyl-; wherein theC₁₋₆alkyl, cycloalkyl, partially unsaturated carbocyclyl, aryl,heteroaryl or heterocycloalkyl, whether alone or as part of asubstituent group is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, carboxy, C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl,halogen substituted C₁₋₄alkyl, cyano substituted C₁₋₄alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, C₁₋₄alkoxy, halogen substituted C₁₋₄alkoxy, nitro, cyano,—R⁵, —O—R⁵, —S—R⁵, —SO₂—R⁵, —SO₂—NR^(P)—R⁵, —NR^(P)—SO₂—R⁵, —NH₂,—N(R^(P))—R⁵, —C(O)—R⁵, —C(O)—NH₂, —C(O)—NR^(P)—R⁵ and —NR^(P)—C(O)—R⁵;wherein R⁵ is selected from the group consisting of C₁₋₄alkyl, aryl,C₁₋₄aralkyl, cycloalkyl, cycloalkyl-C₁₋₄alkyl-, partially unsaturatedcarbocyclyl-C₁₋₄alkyl-, heteroaryl, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl and heterocyclyl-C₁₋₄alkyl-; wherein the aryl,C₁₋₄aralkyl, partially unsaturated carbocyclyl, cycloalkyl, heteroarylor heterocycloalkyl, whether alone or as part of a substituent group isoptionally substituted with one or more substituent independentlyselected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, halogen,hydroxy, carboxy, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, cyano andnitro; wherein R^(P) is selected from the group consisting of hydrogen,C₁₋₈alkyl, hydroxy substituted C₁₋₄alkyl, cycloalkyl, aryl, C₁₋₄aralkyl,heteroaryl and heterocycloalkyl; wherein the cycloalkyl, aryl,heteroaryl or heterocycloalkyl, whether alone or as part of asubstituent group is optionally substituted with one to two substituentsindependently selected from the group consisting of halogen, hydroxy,oxo, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy-carbonyl, nitro, cyano,amino, C₁₋₄alkylamino and di(C₁₋₄alkyl)amino; a is an integer from 0 to1; R¹⁰ is selected from the group consisting of hydroxy, halogen,C₁₋₄alkyl, C₁₋₄alkoxy, halogen substituted C₁₋₄alkyl, halogensubstituted C₁₋₄alkoxy; provided that the halogens on the halogensubstituted C₁₋₄alkyl and the halogen substituted C₁₋₄alkoxy areselected from the group consisting of fluoro and chloro; provided thatwhen R⁰ is hydrogen, R¹ is hydrogen, A¹ is —CH₂—,

is phenyl, Q³ is —O—, R² is methyl, b is an integer selected from 0 to 1and L¹ l is selected from —O—, —NH— or —N(CH₃)—, then R³ is other thanmethyl; or a pharmaceutically acceptable salt thereof.
 3. A compound asin claim 2 wherein R¹ is hydrogen; R¹ is selected from the groupconsisting of hydrogen, methyl and methylcarbonyl; c is an integer from0 to 1; A² is selected from the group consisting of C₁₋₄alkyl; whereinthe C₁₋₄alkyl is optionally substituted with an R^(Y) substituent;wherein R^(Y) is selected from the group consisting of C₁₋₄alkyl, aryl,C₁₋₄aralkyl and cycloalkyl-C₁₋₄alkyl-;

is selected from the group consisting of cycloalkyl, aryl,aryl-C₁₋₄alkyl-, heteroaryl, and heterocycloalkyl; wherein the aryl,heteroaryl or heterocycloalkyl, whether alone or as part of asubstituent group, is optionally substituted with one to twosubstituents independently selected from the group consisting ofC₁₋₄alkyl and C₁₋₄alkoxy; provided that when c is 0, then

is other than aryl or heteroaryl; Q³ is selected from the groupconsisting of —C(O)—, —C(O)O—, —C(O)—NH—, —C(O)—N(C₁₋₈alkyl)-,—C(O)—N(cycloalkyl)-, —NH—C(O)— and —NH—C(O)O—; wherein the cycloalkylis optionally substituted with C₁₋₄alkyl; R² is selected from the groupconsisting of C₁₋₈alkyl, cycloalkyl, cycloalkyl-C₁₋₄alkyl-, aryl,C₁₋₄aralkyl, heteroaryl, heteroaryl-C₁₋₄alkyl-, heterocycloalkyl andheterocycloalkyl-C₁₋₄alkyl-; wherein the C₁₋₈alkyl, cycloalkyl, aryl orheterocycloalkyl, whether alone or as part of a substituent group isoptionally substituted with one to three substituent independentlyselected from the group consisting of halogen, C₁₋₄alkyl, —SO₂—NH₂ andphenyl; b is an integer selected from 0 to 1; L¹ is selected from thegroup consisting of —O—, —S—, —NH—, —C₁₋₄alkyl- and —C₂₋₄alkenyl-; R³ isselected from the group consisting of C₁₋₄alkyl, cycloalkyl,cycloalkyl-C₁₋₄alkyl-, aryl, heteroaryl and heterocycloalkyl; whereinthe cycloalkyl or aryl, whether alone or as art of a substituent groupis optionally substituted with one to two substituents independentlyselected from the group consisting of halogen, hydroxy, carboxy, cyano,nitro, amino, C₁₋₄alkylamino, di(C₁₋₄alkylamino), C₁₋₄alkyl,C₂₋₄alkenyl, C₁₋₄alkoxy, hydroxy substituted C₁₋₄alkyl, halogensubstituted C₁₋₄alkyl, cyano substituted C₁₋₄alkyl, halogen substitutedC₁₋₄alkoxy, —O-aryl, —O—C₁₋₄aralkyl, —S—C₁₋₄alkyl, —SO₂—C₁₋₄alkyl,—C(O)—C₁₋₄alkyl, —C(O)—NH₂, —C(O)—NH(C₁₋₄alkyl), —C(O)—N(C₁₋₄alkyl)₂,—NH—C(O)—C₁₋₄alkyl, —C(O)—NH—C₁₋₄alkyl, —NH—SO₂—C₁₋₄alkyl,—NH—SO₂-phenyl, aryl, C₁₋₄aralkyl, cycloalkyl, cycloalkyl-C₁₋₄alkyl-,heteroaryl, heteroaryl-C₁₋₄alkyl-, heterocycloalkyl andheterocycloalkyl-C₁₋₄alkyl-; wherein the aryl, cycloalkyl, heteroaryl orheterocycloalkyl, whether alone or as part of a substituent group, isoptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₄alkyl and C₁₋₄alkoxy; a is 0;or a pharmaceutically acceptable salt thereof.
 4. A compound as in claim3 wherein R⁰ is hydrogen; R¹ is selected from the group consisting ofhydrogen, methyl and methylcarbonyl; c is an integer from 0 to 1; A² isselected from the group consisting of —CH₂—, —CH(CH₂CH₃)—, —CH(phenyl)-,—CH(benzyl)- and —CH(cyclohexylmethyl)-;

is selected from the group consisting of cyclopentyl, (S)-cyclopentyl,(R)-cyclopentyl, cyclohexyl, (R)-cyclohexyl, (S)-cyclohexyl,trans-cyclohexyl, phenyl, benzyl, 9-fluorenyl, 3-pyrrolidinyl,1-indanyl, 1-(5-methoxy-indanyl)-methyl, 3-piperidinyl, 4-piperidinyl,3-azepinyl, 2-pyridyl, 4-pyridyl, 2-furyl, 2-thienyl and 5-oxazolyl;provided that when c is 0, then

is other than phenyl; Q³ is selected from the group consisting of—C(O)—, —C(O)—NH—, —C(O)—N(CH₃)—, —(R)—C(O)—N(CH₃), —(S)—C(O)—N(CH₃),—C(O)—N(isopropyl)-, —C(O)—N(n-propyl)-, —C(O)—N(isobutyl)-,—C(O)—N(2-ethyl-n-hexyl)-, —C(O)—N(cyclohexyl)-,—C(O)—N(4-methyl-cyclohexyl)-, —C(O)O—, —NH—C(O)— and —NH—C(O)O—; R² isselected from the group consisting of trifluoromethyl, methyl, ethyl,isobutyl, t-butyl, 3-n-heptyl, 4-n-heptyl, 2-ethyl-n-hexyl, cyclopentyl,cyclohexyl, 4-methyl-cyclohexyl, cyclopropyl-methyl,4-aminosulfonyl-phenylethyl, benzhydryl, 1-adamantyl, 2-adamantyl,2-(R)-adamantyl, 2-(S)-adamantyl, 2-decahydro-isoquinolinyl,2-(1-methyl-pyrrolidinyl)-ethyl, 1-piperidinyl and4-(1-methyl-piperidinyl); b is an integer selected from 0 to 1; L¹ isselected from the group consisting of —O—, —S—, —NH—, —CH(CH₃)— and—CH═CH—; R³ is selected from the group consisting of n-pentyl,isopentyl, isobutyl, isopropyl, cyclopentyl, cyclopentyl-methyl, phenyl,2-hydroxy-phenyl, 3-carboxy-phenyl, 2-cyano-phenyl, 2-nitro-phenyl,2-bromo-phenyl, 2-fluoro-phenyl, 2-chloro-phenyl, 2,6-dichloro-phenyl,2-methyl-phenyl, 3-methyl-phenyl, 2-ethyl-phenyl, 4-isopropyl-phenyl,3,4-dimethyl-phenyl, 3,5-dimethyl-phenyl, 2,6-dimethyl-phenyl,2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl,3,4-dimethoxy-phenyl, 2,6-dimethoxy-phenyl, 2-ethoxy-phenyl,3-ethoxy-phenyl, 2-isopropoxy-phenyl, 2-methoxy-5-methyl-phenyl,2-methoxy-6-methyl-phenyl, 2-trifluoromethyl-phenyl,2-trifluoromethoxy-phenyl, 2-methylthio-phenyl, 4-methylthio-phenyl,2-hydroxymethyl-phenyl, 2-cyanomethyl-phenyl, 2-(aminocarbonyl)-phenyl,4-(aminocarbonyl)-phenyl, 2-(dimethylaminocarbonyl)-phenyl,3-(dimethylamino)-phenyl, 4-(dimethylamino)-phenyl,2-allyl-6-methyl-phenyl, 2-allyl-6-ethoxy-phenyl,2-methyl-6-n-propyl-phenyl, 3-(methylcarbonylamino)-phenyl,2-(methylaminocarbonyl)-phenyl, 2-(methylcarbonyl)-phenyl,4-(methylcarbonylamino)-phenyl, 2-(aminocarbonylmethyl)-phenyl,2-(methylsulfonyl)-phenyl,(3-(2-methoxy-4-methyl-phenyl)-sulfonylamino)-phenyl,3-(2,4,6-trimethylphenylsulfonylamino)-phenyl,3-(phenylsulfonylamino)-phenyl, 2-(t-butylaminosulfonyl)-phenyl,2-(t-butylcarbonylamino)-5-methoxy-phenyl,3-(phenylsulfonylamino)-phenyl, 2-phenoxy-phenyl, 3-phenoxy-phenyl,2-benzyloxy-phenyl, 2-(2-benzthiazolyl)-5-methoxy-phenyl,2-(2-benzthiazolyl)-phenyl, 2-(1-pyrrolyl)-phenyl,3-(2-quinolinyl)-phenyl, 2-(1-pyrrolidinyl-methyl)-phenyl,2-cyclopentyl-phenyl, 4-cyclohexyl-phenyl, 4-(4-morpholinyl)-phenyl,3-methoxy-benzyl, 1-naphthyl, 2-naphthyl,2-(5,6,7,8-tetrahydro-naphthyl), 2-biphenyl, 3-biphenyl,2-biphenyl-methyl, 3-pyridyl, 3,4-methylenedioxyphenyl,4(3,5-dimethyl-isoxazolyl), 4-pyrazolyl, 3-thienyl, 3-pyridyl,4-pyridyl, 5-indolyl and 3-benzothienyl; a is 0; or a pharmaceuticallyacceptable salt thereof.
 5. A compound as in claim 4 wherein R⁰ ishydrogen; R¹ is hydrogen; c is an integer from 0 to 1; A² is selectedfrom the group consisting of —CH₂— and —CH(CH₂CH₃)—;

is selected from the group consisting of phenyl, 4-piperidinyl and4-pyridyl; provided that when c is 0, then

is other than phenyl; Q3 is selected from the group consisting of-1-C(O)Q-, -3—C(O)O—, -2-C(O)—N(CH₃)- and -3-C(O)—N(CH₃)—; R² isselected from the group consisting of methyl, ethyl, t-butyl andcyclohexyl; b is an integer from 0 to 1; L¹ is selected from the groupconsisting of —O— and —S—; R³ is selected from the group consisting ofphenyl, 2-bromophenyl, 2-chlorophenyl, 2,6-dichlorophenyl,2-hydroxy-phenyl, 2-hydroxymethyl-phenyl, 2-methoxy-phenyl,3-methoxy-phenyl, 2-ethoxy-phenyl, 2-methylthio-phenyl,2-cyanomethyl-phenyl, 3-(phenyl-sulfonyl-amino)-phenyl,3-(2,4,6-trimethylphenyl-sulfonyl-amino)-phenyl,(3-(2-methoxy-4-methyl-phenyl)-sulfonyl-amino)-phenyl,2-(t-butyl-carbonyl-amino)-5-methoxy-phenyl, 1-naphthyl, 3-thienyl and4-(3,5-dimethylisoxazolyl); a is 0; or a pharmaceutically acceptablesalt thereof.
 6. A compound as in claim 5 wherein R⁰ is hydrogen; R¹ ishydrogen; c is an integer from 0 to 1; A² is selected from the groupconsisting of —CH₂— and —CH(CH₂CH₃)—;

is selected from the group consisting of phenyl and 4-piperidinyl;provided that when c is 0, then

is 4-piperidinyl; Q³ is selected from the group consisting of -1-C(O)O—,-3-C(O)O— and -3-C(O)—N(CH₃)—; R² is selected from the group consistingof methyl, ethyl, t-butyl and cyclohexyl; b is an integer from 0 to 1;L¹ is selected from the group consisting of —O— and —S—; R³ is selectedfrom the group consisting of phenyl, 2-bromophenyl, 2-chlorophenyl,2,6-dichlorophenyl, 2-hydroxy-phenyl, 2-hydroxymethyl-phenyl,2-methoxy-phenyl, 3-methoxy-phenyl, 2-ethoxy-phenyl,2-methylthio-phenyl, 2-cyanomethyl-phenyl,3-(phenyl-sulfonyl-amino)-phenyl, 1-naphthyl and 3-thienyl; a is 0; or apharmaceutically acceptable salt thereof.
 7. A compound as in claim 6wherein R⁰ is hydrogen; R¹ is hydrogen; c is 1; A² is —CH₂—;

is phenyl; Q³ is -3-C(O)—N(CH₃)—; R² is selected from the groupconsisting of methyl, ethyl, t-butyl and cyclohexyl; b is 0; R³ isselected from the group consisting of phenyl, 2-methoxy-phenyl,2-ethoxy-phenyl and 1-naphthyl; a is 0; or a pharmaceutically acceptablesalt thereof.
 8. A compound as in claim 4 wherein R⁰ is hydrogen R¹ isselected from the group consisting of hydrogen and methoxy; c is 1; A²is selected from the group consisting of —CH₂—, —CH(CH₂CH₃)—,—CH(phenyl)— and —CH(cyclohexyl)-;

is selected from the group consisting of phenyl, 2-pyridyl and 2-furyl;Q³ is selected from the group consisting of -3-C(O)—N(CH₃)—,-3-C(O)—N(isopropyl)-, -3-C(O)—N(isobutyl)-, -3-C(O)—N(cyclohexyl)-,-4-C(O)—N(CH₃)- and 5-C(O)—N(CH₃)—; R² is selected from the groupconsisting of isobutyl and cyclohexyl; b is an integer from 0 to 1; L¹is selected from the group consisting of —O—, —S— and —NH—; R³ isselected from the group consisting of phenyl, 2-bromophenyl,2-fluorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2-hydroxyphenyl,2-hydroxymethyl-phenyl, 2-methylphenyl, 3-methylphenyl,2,6-dimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,2,6-dimethoxyphenyl, 2-ethoxyphenyl, 2-trifluoromethylphenyl,2-trifluoromethoxyphenyl, 2-methylthio-phenyl, 2-nitrophenyl,2-cyanophenyl, 2-cyanomethyl-phenyl, 2-phenoxy-phenyl,2-(methyl-carbonyl-amino)-phenyl, 2-(amino-carbonyl)-phenyl,3-(phenyl-sulfonyl-amino)-phenyl, 2-(t-butyl-amino-sulfonyl)-phenyl,2-(t-butyl-carbonyl-amino)-5-methoxy-phenyl, 4-(3,5-dimethyl-soxazolyl),1-naphthyl, 3-thienyl and 3-pyridyl; a is 0; or a pharmaceuticallyacceptable salt thereof
 9. A compound as in claim 8 wherein R⁰ ishydrogen R¹ is hydrogen; c is 1; A² is selected from the groupconsisting of —CH₂—, —CH(CH₂CH₃)— and —CH(cyclohexyl)-;

is selected from the group consisting of phenyl and 2-pyridyl; Q³ isselected from the group consisting of -3-C(O)—N(CH₃)-,-3-C(O)—N(isopropyl)-,-3-C(O)—N(cyclohexyl)- and -4-C(O)—N(CH₃)—; R² iscyclohexyl; b is an integer from 0 to 1; L¹ is —O—; R³ is selected fromthe group consisting of phenyl, 2-bromophenyl, 2-fluorophenyl,2-chlorophenyl, 2-hydroxyphenyl, 2-hydroxymethyl-phenyl, 3-methylphenyl,2-methoxyphenyl, 2-ethoxyphenyl, 2-cyanomethyl-phenyl,2-(t-butyl-carbonyl-amino)-5-methoxy-phenyl, 1-naphthyl and 3-thienyl; ais 0; or a pharmaceutically acceptable salt thereof
 10. A compound as inclaim 9 wherein R⁰ is hydrogen; R¹ is hydrogen; c is 1; A² is —CH₂—;

is phenyl; Q³ is -3-C(O)—N(CH₃)—; R² is cyclohexyl; b is 0; R³ isselected from the group consisting of 2-methoxyphenyl and2-ethoxyphenyl; a is 0; or a pharmaceutically acceptable salt thereof11. A compound of formula (II)

wherein R⁰ is selected from the group consisting of hydrogen, methyl,and CF₃; R¹ is selected from the group consisting of hydrogen, hydroxy,methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxyand methyl-carbonyl; c is an integer from 0 to 1; A² is selected fromC₁₋₄alkyl; wherein the C₁₋₄alkyl is optionally substituted with one ormore R^(Y) substituents; wherein each R^(Y) is independently selectedfrom the group consisting of hydroxy, oxo, C₁₋₄alkyl, C₁₋₄alkoxy,hydroxy substituted C₁₋₄alkyl, amino substituted C₁₋₆alkyl, cycloalkyl,cycloalkyl-C₁₋₄alkyl-, biphenyl, aryl, C₁₋₄aralkyl, heteroaryl,heteroaryl-C₁₋₄alkyl-, heterocycloalkyl, heterocycloalkyl-C₁₋₄alkyl- andspiro-heterocyclyl; wherein the cycloalkyl, aryl, heteroaryl,heterocycloalkyl or spiro-heterocyclyl group, whether alone or as partof a substituent group is optionally substituted with a substituentselected from the group consisting of fluoro, chloro, hydroxy, oxo,carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, —C(O)—(C₁₋₄alkoxy), hydroxy substitutedC₁₋₄alkyl, fluoro substituted C₁₋₄alkyl, fluoro substituted C₁₋₄alkoxy,5-tetrazolyl and 1-(1,4-dihydro-tetrazol-5-one);

is selected from the group consisting of aryl, aryl-C₁₋₄alkyl,cycloalkyl, partially unsaturated carbocyclyl, heteroaryl,heterocycloalkyl and spiro-heterocyclyl; wherein the aryl, cycloalkyl,partially unsaturated carbocyclyl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl group is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₄alkyl, C₁₋₄alkoxy, halogen substituted C₁₋₄alkyl, halogensubstituted C₁₋₄alkoxy, hydroxy substituted C₁₋₄alkyl, hydroxy, carboxy,cyano, nitro, amino, C₁₋₄alkylamino and di(C₁₋₄alkyl)amino; providedthat when c is 0 (i.e. A¹ is absent), then

is other than aryl or heteroaryl; Q³ is selected from the groupconsisting of —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —OC(O)—, —C(O)—NR^(A)—,—NR^(A)—C(O)—, —C(S)—NR^(A), —SO₂—NR^(A), —SO—NR^(A), —OC(O)—NR^(A)—,—NR^(A)—C(O)O— and —O—SO₂—NR^(A)—; wherein each R^(A) is independentlyselected from the group consisting of hydrogen, C₁₋₈alkyl, hydroxysubstituted C₁₋₄alkyl, C₁₋₄aralkyloxy substituted C₁₋₄alkyl, cycloalkyl,aryl, heteroaryl, heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl,heteroaryl-C₁₋₄alkyl-, heterocycloalkyl-C₁₋₄alkyl- andspiro-heterocyclyl; wherein the cycloalkyl, aryl, heteroaryl,heterocycloalkyl or spiro-heterocyclyl, whether alone or as part of asubstituent group is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, oxo, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxy-carbonyl-, nitro, cyano, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —SO₂—N(R^(C)R^(D)), 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one); wherein each R^(C) and R^(D) isindependently selected from the group consisting of hydrogen andC₁₋₄alkyl; R² is selected from the group consisting of C₁₋₁₀alkyl,cycloalkyl, aryl, biphenyl, partially unsaturated carbocyclyl,heteroaryl, heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl,partially unsaturated carbocyclyl-C₁₋₄alkyl-, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl; wherein theC₁₋₁₀alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl, whether alone or as part of a substituent group isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,—C(O)—C₁₋₄alkyl, —C(O)—C₁₋₄aralkyl, —C(O)O—C₁₋₄alkyl,—C(O)O—C₁₋₄aralkyl, —C₁₋₄alkyl-C(O)O—C₁₋₄alkyl, —C₁₋₄alkyl-S—C₁₋₄alkyl,—C(O)—N(R^(L)R^(M)), —C₁₋₄alkyl-C(O)—N(R^(L)R^(M)),—NR^(L)—C(O)—C₁₋₄alkyl, —SO₂—N(R^(L)R^(M)),—C₁₋₄alkyl-SO₂—N(R^(L)R^(M)), C₁₋₆alkyl, fluoro substituted C₁₋₄alkyl,hydroxy substituted C₁₋₄alkyl, carboxy substituted C₁₋₄alkyl,C₁₋₄alkoxy, nitro, cyano, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,phenyl, 5-tetrazolyl and 1-(1,4-dihydro-tetrazol-5-one); wherein thephenyl is optionally substituted with one or more substituentindependently selected from the group consisting of halogen, hydroxy,oxo, carboxy, C(O)O—C₁₋₄alkyl, C(O)—C₁₋₄alkyl, C₁₋₄alkyl, fluorosubstituted C₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano, amino, C₁₋₄alkylaminoand di(C₁₋₄alkyl)amino; wherein each R^(L) and R^(M) is independentlyselected from the group consisting of hydrogen and C₁₋₄alkyl; b is aninteger from 0 to 1; L¹ is selected from the group consisting of —O—,—S(O)₀₋₂—, —NR^(N)—, —C(O)—, —C(S)—, —C₁₋₄alkyl-, -(hydroxy substitutedC₁₋₄alkyl)- and —(C₂ ₄alkenyl)-; wherein R^(N) is selected from thegroup consisting of hydrogen and C₁₋₄alkyl; R³ is selected from thegroup consisting of C₁₋₆alkyl, C₂₋₆alkenyl, cycloalkyl, partiallyunsaturated carbocyclyl, aryl, biphenyl, -heteroaryl, heterocycloalkyl,cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl; wherein theC₁₋₆alkyl, cycloalkyl, partially unsaturated carbocyclyl, aryl,heteroaryl, heterocycloalkyl or spiro-heterocyclyl, whether alone or aspart of a substituent group is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, oxo, carboxy, C₁₋₄alkyl, hydroxy substitutedC₁₋₄alkyl, halogen substituted C₁₋₄alkyl, cyano substituted C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, halogen substituted C₁₋₄alkoxy,nitro, cyano, —R⁵, —O—R⁵, —S—R⁵, —SO₂—R⁵, —SO₂—NR^(P)—R⁵,—NR^(A)—SO₂—R⁵, —NH₂, —N(R^(P))—R⁵, —C(O)—R⁵, —C(O)—NH₂,—C(O)—NR^(P)—R⁵, —NR^(P)—C(O)—R⁵ and —NR^(P)—C(O)O—R⁵; wherein R⁵ isselected from the group consisting of C₁₋₄alkyl, aryl, C₁₋₄aralkyl,partially unsaturated carbocyclyl, cycloalkyl, cycloalkyl-C₁₋₄alkyl-,partially unsaturated carbocyclyl-C₁₋₄alkyl-, heteroaryl,heteroaryl-C₁₋₄alkyl-, heterocycloalkyl and heterocyclyl-C₁₋₄alkyl-;wherein the aryl, C₁₋₄aralkyl, partially unsaturated carbocyclyl,cycloalkyl, heteroaryl or heterocycloalkyl, whether alone or as part ofa substituent group may be optionally substituted with one or moresubstituent independently selected from the group consisting ofC₁₋₄alkyl, C₁₋₄alkoxy, halogen, hydroxy, carboxy, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, cyano and nitro; wherein R^(P) is selected from thegroup consisting of hydrogen, C₁₋₈alkyl, hydroxy substituted C₁₋₄alkyl,C₁₋₄aralkyloxy substituted C₁₋₄alkyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl,heteroaryl-C₁₋₄alkyl-, heterocycloalkyl-C₁₋₄alkyl- andspiro-heterocyclyl; wherein the cycloalkyl, aryl, heteroaryl,heterocycloalkyl or spiro-heterocyclyl, whether alone or as part of asubstituent group is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, oxo, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxy-carbonyl, nitro, cyano, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —SO₂—N(R^(S)R^(T)), 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one); wherein each R^(S) and R^(T) isindependently selected from the group consisting of hydrogen andC₁₋₄alkyl; a is an integer form 0 to 3; each R¹⁰ is independentlyselected from the group consisting of hydroxy, halogen, C₁₋₄alkyl,C₁₋₄alkoxy, halogenated C₁₋₄alkyl, halogenated C₁₋₄alkoxy,—C(O)—NR^(V)R^(W), —SO₂—NR^(V)R^(W), —C(O)—C₁₋₄alkyl and —SO₂-C₁₋₄alkyl;wherein each R^(V) and R^(W) is independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl; alternatively R^(V) and R^(W) aretaken together with the N atom to which they are bound to form a 5 to 6membered saturated, partially unsaturated or aromatic ring structure;provided that the halogens on the halogenated-C₁₋₄alkyl and thehalogenated C₁₋₄alkoxy are selected from chloro or fluoro; provided thatwhen R⁰ is hydrogen, R¹ is hydrogen, A¹ is —CH₂—,

is phenyl, Q³ is —O—, R² is methyl, b is an integer selected from 0 to 1and L¹ is selected from —O—, —NH— or —N(CH₃)—, then R³ is other thanmethyl; or a pharmaceutically acceptable salt thereof.
 12. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of claim
 1. 13. A pharmaceutical composition madeby mixing a compound of claim 1 and a pharmaceutically acceptablecarrier.
 14. A process for making a pharmaceutical compositioncomprising mixing a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 15. A method of treating a disorder mediated byβ-secretase, comprising administering to a subject in need thereof, atherapeutically effective amount of the compound of claim
 1. 16. Themethod of claim 15, wherein the disorder mediated by β-secretase isselected from the group consisting of Alzheimer's disease (AD), mildcognitive impairment, senility, dementia, dementia with Lewy bodies,Down's syndrome, dementia associated with Parkinson's disease anddementia associated with beta-amyloid.
 17. A method of treating adisorder mediated by β-secretase, comprising administering to a subjectin need thereof, a therapeutically effective amount of the compositionof claim
 12. 18. A method of treating a condition selected from thegroup consisting of Alzheimer's disease (AD), mild cognitive impairment,senility, dementia, dementia with Lewy bodies, Down's syndrome, dementiaassociated with Parkinson's disease and dementia associated withbeta-amyloid, comprising administering to a subject in need thereof, atherapeutically effective amount of the compound of claim
 1. 19. The useof a compound as in claim 1 for the preparation of a medicament fortreating: (a) Alzheimer's disease (AD), (b) mild cognitive impairment,(c) senility, (d) dementia, (e) dementia with Lewy bodies, (f) Down'ssyndrome, (g) dementia associated with Parkinson's disease and (h)dementia associated with beta-amyloid, in a subject in need thereof. 20.A compound of formula (CII)

wherein R⁰ is selected from the group consisting of hydrogen, methyl,and CF₃; c is an integer from 0 to 1; A² is selected from the groupconsisting of C₁₋₄alkyl; wherein the C₁₋₄alkyl is optionally substitutedwith one or more R^(Y) substituents; wherein each R^(Y) is independentlyselected from the group consisting of hydroxy, oxo, C₁₋₄alkyl,C₁₋₄alkoxy, hydroxy substituted C₁₋₄alkyl, amino substituted C₁₋₆alkyl,cycloalkyl, cycloalkyl-C₁₋₄alkyl-, biphenyl, aryl, C₁₋₄aralkyl,heteroaryl, heteroaryl-C₁₋₄alkyl-, heterocycloalkyl,heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl; wherein thecycloalkyl, aryl, heteroaryl, heterocycloalkyl or spiro-heterocyclylgroup, whether alone or as part of a substituent group is optionallysubstituted with one or more substituents independently selected fromthe group consisting of fluoro, chloro, hydroxy, oxo, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, —C(O)O-(C₁₋₄alkyl), hydroxy substitutedC₁₋₄alkyl, fluoro substituted C₁₋₄alkyl, fluoro substituted C₁₋₄alkoxy,5-tetrazolyl and 1-(1,4-dihydro-tetrazol-5-one);

is selected from the group consisting of aryl, aryl-C₁₋₄alkyl,cycloalkyl, partially unsaturated carbocyclyl, heteroaryl,heterocycloalkyl and spiro-heterocyclyl; wherein the aryl, cycloalkyl,partially unsaturated carbocyclyl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl group, whether alone or as part of a substituentgroup, is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₄alkyl,C₁₋₄alkoxy, halogen substituted C₁₋₄alkyl, halogen substitutedC₁₋₄alkoxy, hydroxy substituted C₁₋₄alkyl, hydroxy, carboxy, cyano,nitro, amino, C₁₋₄alkylamino and di(C₁₋₄alkyl)amino; provided that whenc is 0, then

is other than aryl or heteroaryl; Q³ is selected from the groupconsisting of —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —OC(O)—, —C(O)—NR^(A),—NR^(A)—C(O)—, —C(S)—NR^(A), —SO₂—NR^(A)—, —SO—NR^(A), —OC(O)—NR^(A)—,—NR^(A)—C(O)O— and —O—SO₂—NR^(A)—; wherein each R^(A) is independentlyselected from the group consisting of hydrogen, C₁₋₈alkyl, hydroxysubstituted C₁₋₄alkyl, C₁₋₄aralkyloxy substituted C₁₋₄alkyl, cycloalkyl,aryl, heteroaryl, heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl,heteroaryl-C₁₋₄alkyl-, heterocycloalkyl-C₁₋₄alkyl- andspiro-heterocyclyl; wherein the cycloalkyl, aryl, heteroaryl,heterocycloalkyl or spiro-heterocyclyl, whether alone or as part of asubstituent group is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, oxo, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxy-carbonyl, nitro, cyano, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —SO₂—N(R^(C)R^(D)), 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one); wherein each R^(C) and R^(D) isindependently selected from the group consisting of hydrogen andC₁₋₄alkyl; R² is selected from the group consisting of C₁₋₈alkyl,cycloalkyl, aryl, biphenyl, partially unsaturated carbocyclyl,heteroaryl, heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl,partially unsaturated carbocyclyl-C₁₋₄alkyl-, heteroaryl-C₁₋₄alkyl-,heterocycloalkyl-C₁₋₄alkyl- and spiro-heterocyclyl; wherein theC₁₋₈alkyl, cycloalkyl, aryl, partially unsaturated carbocyclyl,heteroaryl, heterocycloalkyl or spiro-heterocyclyl, whether alone or aspart of a substituent group is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, oxo, carboxy, —C(O)—C₁₋₄alkyl, —C(O)—C₁₋₄aralkyl,—C(O)O—C₁₋₄alkyl, —C(O)O—C₁₋₄aralkyl, —C₁₋₄alkyl-C(O)O—C₁₋₄alkyl,—C₁₋₄alkyl-S—C₁₋₄alkyl, —C(O)—N(R^(L)R^(M)),—C₁₋₄alkyl-C(O)—N(R^(L)R^(M)), —NR^(L)—C(O)—C₁₋₄alkyl,—SO₂—N(R^(L)R^(M)), —C₁₋₄alkyl-SO₂—N(R^(L)R^(M)), C₁₋₆alkyl, fluorosubstituted C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, carboxysubstituted C₁₋₄alkyl, C₁₋₄alkoxy, —O—C₁₋₄aralkyl,—O-(tetrahydropyranyl), —NH—OC(O)—CH₂-(tetrahydropyranyl),—N(CH₃)—OC(O)—CH₂-(tetrahydropyranyl), nitro, cyano, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, phenyl, 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one); wherein the phenyl or tetrahydropyranylis optionally substituted with one or more substituent independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,C(O)O—C₁₋₄alkyl, C(O)—C₁₋₄alkyl, OC(O)—C₁₋₄alkyl,-C₁₋₄alkyl-OC(O)—C₁₋₄alkyl, —O—C₁₋₄aralkyl, C₁₋₄alkyl, fluorosubstituted C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, C₁₋₄alkoxy, nitro,cyano, amino, C₁₋₄alkylamino and di(C₁₋₄alkyl)amino; wherein each R^(L)and R^(M) is independently selected from the group consisting ofhydrogen and C₁₋₄alkyl; b is an integer from 0 to 1; L¹ is selected fromthe group consisting of —O—, —S(O)₀₋₂—, —NR^(N)—, —C(O)—, —C(S)—,—C₁₋₄alkyl-, -(hydroxy substituted C₁₋₄alkyl)- and -(C₂-₄alkenyl)-;wherein R^(N) is selected from the group consisting of hydrogen andC₁₋₄alkyl; R³ is selected from the group consisting of C₁₋₆alkyl,C₂₋₆alkenyl, cycloalkyl, partially unsaturated carbocyclyl, aryl,biphenyl, heteroaryl, heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-,C₁₋₄aralkyl, heteroaryl-C₁₋₄alkyl-, heterocycloalkyl-C₁₋₄alkyl- andspiro-heterocyclyl; wherein the C₁₋₆alkyl, cycloalkyl, partiallyunsaturated carbocyclyl, aryl, heteroaryl, heterocycloalkyl orspiro-heterocyclyl, whether alone or as part of a substituent group isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, carboxy,C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, halogen substituted C₁₋₄alkyl,cyano substituted C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,halogen substituted C₁₋₄alkoxy, nitro, cyano, —R⁵, —O—R⁵, —S—R⁵,—SO₂—R⁵, —SO₂—NR^(P)—R⁵, —NR^(P)—SO₂—R⁵, —NH₂, —N(R^(P))—R⁵, —C(O)—R⁵,—C(O)—NH₂, —C(O)—NR^(P)—R⁵, —NR^(P)—C(O)—R⁵ and —NR^(P)—C(O)O—R⁵;wherein R⁵ is selected from the group consisting of C₁₋₄alkyl, aryl,C₁₋₄aralkyl, partially unsaturated carbocyclyl, cycloalkyl,cycloalkyl-C₁₋₄alkyl-, partially unsaturated carbocyclyl-C₁₋₄alkyl-,heteroaryl, heteroaryl-C₁₋₄alkyl-, heterocycloalkyl andheterocyclyl-C₁₋₄alkyl-; wherein the aryl, partially unsaturatedcarbocyclyl, cycloalkyl, heteroaryl or heterocycloalkyl, whether aloneor as part of a substituent group is optionally substituted with one ormore substituent independently selected from the group consisting ofC₁₋₄alkyl, C₁₋₄alkoxy, halogen, hydroxy, carboxy, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, cyano and nitro; wherein R^(P) is selected from thegroup consisting of hydrogen, C₁₋₈alkyl, hydroxy substituted C₁₋₄alkyl,C₁₋₄aralkyloxy substituted C₁₋₄alkyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl, cycloalkyl-C₁₋₄alkyl-, C₁₋₄aralkyl,heteroaryl-C₁₋₄alkyl-, heterocycloalkyl-C₁₋₄alkyl- andspiro-heterocyclyl; wherein the cycloalkyl, aryl, heteroaryl,heterocycloalkyl or spiro-heterocyclyl, whether alone or as part of asubstituent group is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, oxo, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxy-carbonyl, nitro, cyano, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —SO₂—N(R^(S)R^(T)), 5-tetrazolyl and1-(1,4-dihydro-tetrazol-5-one); wherein each R^(S) and R^(T) isindependently selected from the group consisting of hydrogen andC₁₋₄alkyl; a is an integer form 0 to 3; each R⁰ is independentlyselected from the group consisting of hydroxy, halogen, C₁₋₄alkyl,C₁₋₄alkoxy, halogen substituted C₁₋₄alkyl, halogen substitutedC₁₋₄alkoxy, —C(O)—NR^(V)R^(W), —SO₂—NR^(V)R^(W), —C(O)—C₁₋₄alkyl and—SO₂—C₁₋₄alkyl; wherein each R^(V) and R^(W) is independently selectedfrom the group consisting of hydrogen and C₁₋₄alkyl; alternatively R^(V)and R^(W) are taken together with the N atom to which they are bound toform a 5 to 6 membered saturated, partially unsaturated or aromatic ringstructure; provided that the halogens on the halogen substitutedC₁₋₄alkyl or the halogen substituted C₁₋₄alkoxy are selected from thegroup consisting of chloro and fluoro; or a pharmaceutically acceptablesalt thereof.